Signs and symptoms of ascending cholangitis (also known as acute cholangitis) develop due to the obstruction of the biliary tree (by gallstones or choledocholithiasis, tumors or benign strictures are known as pathogenic mechanisms) and secondary bacterial colonization of the bile ducts from the gastrointestinal tract or the portal venous system [1] [2]. As a result, bacteria are able to reproduce and proliferate in this tight environment (as bile is not capable of flushing them back into the duodenum along its pathway), causing an intense inflammatory reaction and symptoms of abdominal pain, jaundice and fever, known as the Charcot's triad [3] [4] [5]. Although this clinical entity was described more than 100 years ago, most recent guidelines have proposed the exclusion of abdominal pain from constitutive features of acute cholangitis, because of a rather low report rate by patients [5] [6]. Indeed, the presence of a complete Charcot's triad ranges from 15.4–72.0%, which is why fever and jaundice remain the most important features [4]. Ascending cholangitis is life-threatening, with mortality rates being 2.5-3.5%, but in the absence of an early diagnosis, dissemination of bacteria in the systemic circulation and sepsis can occur, in which case mortality rates rise to 84-100% without immediate initiation of directed therapy [3] [5] [7]. In fact, septic encephalopathy is seen in up to 9% of cholangitis patients and is manifested as loss of consciousness and shock in most severe cases [5] [7]. Furthermore, some authors add hypotension and altered mental status to the Charcot triad's to form the Reynold's pentad, another diagnostic tool used to identify patients with ascending cholangitis [3] [8].

• Hemophilia A

  Guillain-Barré syndrome Hashimoto thyroiditis Head and neck examination Headache Health care system Hearing loss Heart Heatstroke Helminth infections Hemochromatosis Hemolytic anemia Hemolytic disease of the fetus and newborn Hemolytic uremic syndrome Hemophilia [amboss.com]

• Fever

  Indeed, the presence of a complete Charcot's triad ranges from 15.4–72.0%, which is why fever and jaundice remain the most important features. [symptoma.com]

  Fever and Skin Rash 292 Fever and the Renal Transplant Recipient 301 Fever Following Travel Abroad 306 Hyperpyrexia and Hyperthermia 316 Fever in the Granulocytopenic Patient 319 Fever of Unknown Origin 325 Recurrent Furunculosis 333 Postoperative Fever [books.google.com]

  One of the main causes of ascending cholangitis is bacteria, resulting in symptoms such as fever, jaundice and pain. [diethealthclub.com]

  […] chol·an·gi·tis len·ta low-grade bacterial infection of the biliary tract; sometimes causes fever of unknown origin. ascending cholangitis Acute bile duct inflammation. [medical-dictionary.thefreedictionary.com]

  IV Ampicillin-gentamicin is administered, fluid resuscitation is initiated, and over 24 hours the patient’s fever improves. [medbullets.com]

• Chills

  Clinical findings Right upper quadrant pain that may radiate to the shoulder, variable severity, nausea, vomiting, constipation, episodic chills, fever, slow pulse, Murphy sign, anorexia, weight loss; spontaneous remission is rare. [medical-dictionary.thefreedictionary.com]

  SYNONYMS Biliary sepsis Ascending cholangitis Suppurative cholangitis SYMPTOMS Pain, chills, and jaundice ( Charcot triad ) are the cardinal symptoms of cholangitis. Pain may be absent. [encyclopedia.lubopitko-bg.com]

  […] coli, Klebsiella, Streptococcus, Enterobacter, Pseudomonas Other causes: HIV/AIDS cholangiopathy, parasitic infections (Ascaris lumbricoides) Presentation Charcot’s Triad: Fever, RUQ pain and jaundice (neither sensitive nor specific) Symptoms Fever/chills [coreem.net]

  Fever and chills. Dark urine and clay-colored stools. Nausea and vomiting. Yellowing of the skin (jaundice), which may come and go. Quick diagnosis and treatment are very important. [medlineplus.gov]

  Intermittent fever accompanied by chills, right upper quadrant abdominal pain, and jaundice have been established as Charcot's triad. [patient.info]

• Rigor

  Presentation – rigors, fever, abdominal pain, jaundice Treatment It is a medical emergency. [almostadoctor.co.uk]

  Signs and symptoms A person with cholangitis may complain of abdominal pain (particularly in the right upper quadrant of the abdomen ), fever, rigors (uncontrollable shaking) and a feeling of uneasiness ( malaise ). [ipfs.io]

  Ascending Cholangitis Signs and Symptoms AC patients may experience problems like: Abdominal pain Rigors Fever Malaise, or a feeling of uneasiness Jaundice may also be reported in some cases. [medicalsubstance.com]

  Signs and symptoms[edit] A person with cholangitis may complain of abdominal pain (particularly in the right upper quadrant of the abdomen), fever, rigors (uncontrollable shaking) and a feeling of uneasiness (malaise). [en.wikipedia.org]

  Other symptoms include the following: Jaundice Fever, chills, and rigors Abdominal pain Pruritus Acholic or hypocholic stools Malaise The patient's medical history may be helpful. [emedicine.medscape.com]

• Abdominal Pain

  Principal symptoms include abdominal pain, fever, and jaundice, known as the Charcot's triad, but additional clinical signs, as well as imaging studies, are necessary to confirm the diagnosis. [symptoma.com]

  For Additional Reading: Cholangitis: Pearls & Pitfalls http://www.emdocs.net/cholangitis-pearls-pitfalls/ Cholangitis: Deadly Cause of Right Upper Quadrant Abdominal Pain Cholangitis: Deadly Cause of Right Upper Quadrant Abdominal Pain [emdocs.net]

  A 73-year-old man with abdominal pain and vomiting was admitted to the emergency room. His medical history was significant for subtotal gastrectomy with Billroth II anastomosis for benign gastric ulcer perforation 40 years prior. [ncbi.nlm.nih.gov]

  One symptom is abdominal pain in the upper region, especially in the middle or right upper side region. This pain usually comes and goes and is crampy, sharp or dull. [diethealthclub.com]

  Charcot's triad: Fever Abdominal pain Jaundice Reynolds pentad: Fever Abdominal pain Jaundice Confusion Hypotension Charcot described the original triad in 1877. [derangedphysiology.com]

• Nausea

  Clinical findings Right upper quadrant pain that may radiate to the shoulder, variable severity, nausea, vomiting, constipation, episodic chills, fever, slow pulse, Murphy sign, anorexia, weight loss; spontaneous remission is rare. [medical-dictionary.thefreedictionary.com]

  Other symptoms include fever, chills, clay-colored stools, vomiting and nausea, dark urine, and skin yellowing (jaundice). Primary sclerosing cholangitis signs or symptoms may not be seen in the early stages. [diethealthclub.com]

  It can also be accompanied by: jaundice pale stools dark urine abdominal pain nausea See your doctor if you have itching in pregnancy. [healthline.com]

• Vomiting

  A 73-year-old man with abdominal pain and vomiting was admitted to the emergency room. His medical history was significant for subtotal gastrectomy with Billroth II anastomosis for benign gastric ulcer perforation 40 years prior. [ncbi.nlm.nih.gov]

  Clinical findings Right upper quadrant pain that may radiate to the shoulder, variable severity, nausea, vomiting, constipation, episodic chills, fever, slow pulse, Murphy sign, anorexia, weight loss; spontaneous remission is rare. [medical-dictionary.thefreedictionary.com]

  The abdominal pain is often associated with lumbago irradiating to the thighs, and with nausea, vomiting and relentless constipation. [orpha.net]

  Other symptoms include fever, chills, clay-colored stools, vomiting and nausea, dark urine, and skin yellowing (jaundice). Primary sclerosing cholangitis signs or symptoms may not be seen in the early stages. [diethealthclub.com]

  The pain lasts longer than 6h and is usually associated with nausea/vomiting, fever and right upper quadrant pain. Choledocholithiasis – gallstones in the common bile duct. [sketchymedicine.com]

• Clay-Colored Stool

  Dark urine and clay-colored stools. Nausea and vomiting. Yellowing of the skin (jaundice), which may come and go. Quick diagnosis and treatment are very important. Antibiotics to cure infection are the first treatment done in most cases. [medlineplus.gov]

  Other symptoms include fever, chills, clay-colored stools, vomiting and nausea, dark urine, and skin yellowing (jaundice). Primary sclerosing cholangitis signs or symptoms may not be seen in the early stages. [diethealthclub.com]

  People who are at a greater risk of developing an infection in the bile duct includes anyone who has: Signs and Symptoms The signs and symptoms of acute cholangitis are often similar to that of gallstones and can include: Back pain Chills Clay-colored [verywellhealth.com]

  Each person’s symptoms may vary, and may be non-specific or severe, including: Pain in the upper right part of your belly (abdomen) Fever Chills Yellowing of the skin and eyes (jaundice) Nausea and vomiting Clay-colored stools Dark urine Low blood pressure [hopkinsmedicine.org]

• Loss of Appetite

  They include consumption of large amounts of alcohol, loss of appetite, nausea, and vomiting. [msdmanuals.com]

  Other less common signs and symptoms of cholestasis of pregnancy may include: Yellowing of the skin and whites of the eyes (jaundice) Nausea Loss of appetite When to see a doctor Contact your pregnancy care provider immediately if you begin to feel persistent [mayoclinic.org]

  Itching, particularly on the hands and feet (often is the only symptom noticed) Dark urine color Pain in the right upper quadrant (RUQ), without gallstones Pale/Light coloring of bowel movements Fatigue or exhaustion Loss of appetite Depression Less common [americanpregnancy.org]

• Hypotension

  HISTORY • Gallstones, CBD stones (28%-70%) • Recent cholecystectomy • Endoscopic manipulation or ERCP, cholangiogram • History of cholangitis • Immunocompromised • Malignancy (10-57%) • Sepsis • Hypotension (30%)- has been reported as the only symptom [slideshare.net]

  In the more severe, life-threatening form, known as toxic cholangitis or cholangitis with sepsis, patients have purulent biliary tree contents, as well as evidence of sepsis, hypotension, multi-organ failure, and mental status changes. [1] Boey JH, Way [bestpractice.bmj.com]

  A minority of patients present in shock with hypotension and altered mentation. There is usually a leukocytosis, and the alkaline phosphatase and bilirubin levels are generally elevated. [ncbi.nlm.nih.gov]

  Furthermore, some authors add hypotension and altered mental status to the Charcot triad's to form the Reynold's pentad, another diagnostic tool used to identify patients with ascending cholangitis. [symptoma.com]

  […] carcinoma triad: (1) hematuria, (2) flank pain, (3) abdominal mass Note this triad only appears 10% of the time Charcot’s triad for ascending cholangitis: (1) fever (2) RUQ pain (3) Jaundice Reynaud’s pentad for ascending cholangitis: Charcot’s triad + hypotension [theweeklymnemonic.wordpress.com]

• Tachycardia

  […] lumbricoides) Presentation Charcot’s Triad: Fever, RUQ pain and jaundice (neither sensitive nor specific) Symptoms Fever/chills Nausea/vomiting Abdominal pain Physical Exam RUQ tenderness to palpation Peritoneal signs are variable Jaundice Frank sepsis (fever, tachycardia [coreem.net]

  28%-70%) • Recent cholecystectomy • Endoscopic manipulation or ERCP, cholangiogram • History of cholangitis • Immunocompromised • Malignancy (10-57%) • Sepsis • Hypotension (30%)- has been reported as the only symptom in patients on glucocorticoids • Tachycardia [slideshare.net]

  Tachycardia and hyponatremia are common during attacks. In cases with cardiac arrhythmia and respiratory paralysis (rare), attacks can be fatal. [orpha.net]

  […] cholecystectomy ERCP or cholangiogram previous cholangitis immunocompromise malignancy CLINICAL FEATURES History fever (>80%) abdominal pain (especially RUQ) (>80%) nausea and vomiting, malaise predisposing factors and history of an underlying cause Examination tachycardia [litfl.com]

• Jaundice

  Indeed, the presence of a complete Charcot's triad ranges from 15.4–72.0%, which is why fever and jaundice remain the most important features. [symptoma.com]

  One of the main causes of ascending cholangitis is bacteria, resulting in symptoms such as fever, jaundice and pain. [diethealthclub.com]

  We seen patients jaundiced with common duct stones quite frequently in surgical practice but it's quite rare for a patient to progress so quickly to septic shock. [buckeyesurgeon.com]

  Jaundice results from a pathologic process that interferes with the normal metabolism and excretion of bilirubin (Figure 158-1). [accessmedicine.mhmedical.com]

  stone in CBD/ obstructive jaundice(jaundice is big thing here)/ RUQ or epigastric pain/ total and direct bilirubin elevated as well as alkaline phosphatase/ can lead to cholangitis/ usg done but cant proficiently see CBD so gold standard is ERCP cholangitis [usmleforum.com]

• Biliary Colic

  DDx Biliary leaks Liver abscess Infected choledochal cysts Cholecystitis Mirizzi syndrome Right lower lobe pneumonia/empyema Lab values Biliary Colic Cholecystitis Choledocholithiasis Cholangitis Gallbladder Pancreatitis WBC – ↑ ↑ ↑↑ ↑ AST – – ↑ ↑ ↑ ALT [sketchymedicine.com]

  These stones cause biliary colic, biliary obstruction, gallstone pancreatitis, or cholangitis (bile duct infection and inflammation). Cholangitis, in turn, can lead to strictures, stasis, and choledocholithiasis. [msdmanuals.com]

  Compare & contrast the S & Sx of RUQ P, fever/^WCC, & jaundice in biliary colic, acute cholecystitis, & cholangitis. [goconqr.com]

• Scleral Icterus

  Initial Presentation: Jaundice Abdominal pain Fever Vital Signs: Fever can be present given this is an infectious process Dermatological Exam: Scleral icterus Jaundice Abdominal Exam: Abdominal tenderness: can commonly be in the right upper quadrant. [stepwards.com]

  She has scleral icterus and jaundice (worsened per family). The patient grimaces on palpation of the right upper quadrant. Initial VS: BP 90/68, HR 147, T 103.2 Rectal, RR 24, SpO2 95% on room air. [emdocs.net]

  It results in jaundice, which can be detected by scleral icterus at a concentration as low as 2 mg/dL, and by dark urine. [emedicine.medscape.com]

• Hepatomegaly

  Physical examination may reveal the following: Fever (90%), although elderly patients may have no fever RUQ tenderness (65%) Mild hepatomegaly Jaundice (60%) Mental status changes (10-20%) Sepsis Hypotension (30%) Tachycardia Peritonitis (uncommon, and [emedicine.medscape.com]

  Tender hepatomegaly can be seen in viral hepatitis, congestive heart failure, and alcoholic hepatitis. In choledocholithiasis and cholecystitis, right upper quadrant (RUQ) tenderness is appreciated. [ncbi.nlm.nih.gov]

• Pruritus

  Ultraviolet B phototherapy has been successfully used to treat pruritus. [emedicine.medscape.com]

  Prominent features of cholestasis are pruritus and malabsorption of fat and fat-soluble vitamins. [ncbi.nlm.nih.gov]

  This is sometimes called pruritus. It may be all over the body. But it is more common on the palms of the hands and soles of the feet. It may also be worse at night. [stanfordchildrens.org]

  This condition causes severe itchiness (pruritus) in the expectant mother. The itchiness usually begins on the palms of the hands and the soles of the feet and then spreads to other parts of the body. [ghr.nlm.nih.gov]

  The patient may also report acholic (putty-coloured) stools and pruritus. A history of gallstones, CBD stones, recent cholecystectomy, ERCP or other invasive procedures, HIV or AIDS may assist the diagnosis. [patient.info]

• Dark Urine

  It can also be accompanied by: jaundice pale stools dark urine abdominal pain nausea See your doctor if you have itching in pregnancy. [healthline.com]

  Obstruction of the biliary system can hinder excretion of bilirubin into the gut and simultaneously exceed the processing ability of the kidneys, leading to pale stools and dark urine. [accessmedicine.mhmedical.com]

  Jaundice, dark urine, light-colored stools, and generalized itchiness are characteristic symptoms of cholestasis. Jaundice results from excess bilirubin deposited in the skin, and dark urine results from excess bilirubin excreted by the kidneys. [msdmanuals.com]

Acute deterioration of patients that present with jaundice and fever (as well as abdominal pain) must raise clinical suspicion of an inflammatory process in the biliary tree, especially if loss of consciousness or an altered mental state is also present [3]. After obtaining a detailed patient history (if patients are unconscious, friends or family who bring the patient to the hospital can provide valuable information). Conducting a thorough physical examination and a complete laboratory workup is mandatory. A complete blood count (CBC) will almost always show leukocytosis [5], whereas inflammatory parameters - C-reactive protein (CRP), erythrocyte sedimentation rate (ESR), and fibrinogen will all be elevated depending on the duration and severity of the infection. Alkaline phosphatase (ALP), bilirubin, and pancreatic amylase levels may be elevated in severe cases [8]. At the same time, blood cultures should be drawn, and they are likely to be positive in the majority of the cases [5]. Bacterial pathogens that cause ascending cholangitis are principally gram-negative Enterobacteriaceae (Escherichia coli, Enterobacter spp, and Klebsiella spp), while gram-positive microorganisms (eg. Enterococcus sp) and anaerobes (Bacteroides spp, Clostridia, and Fusobacterium spp) are less common [8]. On the other hand, imaging studies must be performed early on, including ultrasonography and computed tomography (CT), which is recommended as a first-line procedure [4]. Multidetector CT (MDCT) has shown even greater specificity and sensitivity and should be performed whenever possible, while magnetic resonance cholangiopancreatography (MRCP) is also mentioned as a reliable method to diagnose the condition [3] [4].

• Neutrophilia

  […] of cases): fever, RUQ pain and jaundice Reynold’s pentad (~5% of cases): Charcot triad plus altered mental state and shock INVESTIGATIONS Bedside blood gas including glucose (liver failure, HAGMA, lactate) ECG (myocardial ischaemia) Laboratory FBC (neutrophilia [litfl.com]

  Biochemical analyses demonstrated a leukocytosis and neutrophilia; haemoglobin (Hb) 11.9 g/dL, white blood cell count (WCC) 13.9 × 10 9 /L, neutrophils 11.4 × 10 9 /L. An acute phase response was evident with C-reactive protein (CRP) 131 mg/L. [jmedicalcasereports.biomedcentral.com]

It is unclear as to which type of the fistula needs surgical treatment. [ncbi.nlm.nih.gov]

Cholangitis Treatment It is important that cholangitis is diagnosed in time and appropriate treatment be administered. In the initial stages cholangitis, treatment guidelines recommend that antibiotics be used to treat the problem. [diethealthclub.com]

Antibiotics alone do not provide sufficient treatment in the majority of patients. Drainage of the biliary tree is the most critical step in management. [blood-test.biz]

It may worsen the prognosis, with an increase in mortality, secondary failure of restoration of bile flow, and possible exacerbation of portal hypertension. [clinicaltrials.gov]

Overall prognosis depends on the severity of the illness at the time of presentation and the cause of the biliary obstruction. [ncbi.nlm.nih.gov]

Treatment and prognosis Treatment involves appropriate antibiotic therapy and biliary tree decompression (usually either via ERCP or PTC). Mortality rates are between 50-90% for severe acute cholangitis 5,6. [radiopaedia.org]

Prognosis The prognosis depends on several factors, including the following [6] : Early recognition and treatment of cholangitis Response to therapy Underlying medical conditions of the patient Mortality rate ranges from 5-10%, with a higher mortality [emedicine.medscape.com]

Liver Biopsy Helpful in intrahepatic cholestasis to evaluate for various possible underlying etiologies. Treatment / Management Management of cholestatic jaundice widely depends upon underlying etiology and type of cholestasis. [ncbi.nlm.nih.gov]

PM Treatment of acute cholangitis is directed toward the 2 main etiologic components of the disease: biliary infection and obstruction. [gastroenterologyandhepatology.net]

Other etiologies include strictures and tumors. The bile flow is stanched and the patient will become jaundiced. [buckeyesurgeon.com]

Etiology immunity / dysimmunity acute rejection of liver allograft Kawasaki disease viral infections Cytomegalovirus (neonate) bacterial infections Salmonellosis Syphilis, secondary Toxic shock syndrome Tuberculosis Pyogenic abscess Reactive changes, [humpath.com]

Poor prognostic factors Various factors from literature to suggest poor prognosis 10,12,13,14 high fever >39°C shock organ dysfunction advance age >75 years mental confusion malignancy as etiology medical comorbidities hyperbilirubinemia ≥2.2 mg/dl reduced [radiopaedia.org]

EPIDEMIOLOGY & DEMOGRAPHICS INCIDENCE (IN U.S.): Complicates approximately 2% of cases of cholelithiasis • Other causes: prior biliary tract surgery with secondary stenosis, tumor (usually arising from the pancreas or biliary tree), and parasitic infections [encyclopedia.lubopitko-bg.com]

Epidemiology: Reportedly occurs in 50,000-75,000 individuals in the U.S. annually; mortality estimated as 5%. 1 Presentation: Fever is the most common presenting symptom (90% of cases 1 ). [emdocs.net]

TG13 current terminology, etiology, and epidemiology of acute cholangitis and cholecystitis. J Hepatobiliary Pancreat Sci. 2013;20:8–23. [PubMed] [Google Scholar] 8. Shaffer EA. Gallstone disease: Epidemiology of gallbladder stone disease. [ncbi.nlm.nih.gov]

Mortality rate 5-10% Hepatobiliary Tract Anatomy Pathophysiology Bile duct develops an obstruction Obstruction may be incomplete (more common) or complete Causes: Gallstones (most common), malignancy, benign stricture, iatrogenic (i.e. [coreem.net]

For related pathophysiology, please see the Cholelithiasis and Cholecystitis and Biliary Colic articles. [emedicine.medscape.com]

Definitions, pathophysiology, and epidemiology of acute cholangitis and cholecystitis: Tokyo Guidelines. J Hepa- tobiliary Pancreat Surg. 2007;14:15-26. https://doi.org/10.1007/s00534-006-1152-y 35. Elwood DR. Cholecystitis. [revistacirugia.org]

Pharmacotherapy: A Pathophysiologic Approach (5th Ed). DiPiro JT, Talbert RL, Yee GC et al (Eds). McGraw-Hill: New York, 2002, pg. 273-303. [nlm.nih.gov]

[…] of Influenza 480 AIDS 78 Transmission and Prevention of HIV Infection 489 Primary HIV infection 496 Treatment of Pneumocystis Carinii Pneumonia in AIDS 499 HIV1 and Infections of the Central Nervous System 504 Fever in the HIVinfected Patient 516 Prevention [books.google.com]

Acute cholangitis and gallstone pancreatitis are two major complications that require prompt recognition and timely intervention to limit morbidity and prevent mortality or recurrence. [indiana.pure.elsevier.com]

Abstract An intussusception-type antireflux valve was created in the Roux-en-Y loop in 23 infants with biliary atresia (17 new cases, and six others after episodes of ascending cholangitis) and 10 patients with congenital bile duct dilatation, in order to prevent [ncbi.nlm.nih.gov]

( 18787839 ) Televantou D....Hytiroglou P. 2008 19 Management of ascending cholangitis. ( 17556149 ) Kinney T.P. 2007 20 New strategy to prevent ascending cholangitis in larger choledochoduodenal fistula. ( 16922901 ) Li Z.H....Dong J. 2006 21 Acute ascending [malacards.org]

1. Mosler P. Diagnosis and management of acute cholangitis. Curr Gastroenterol Rep. 2011;13(2):166-172.
2. Kiriyama S, Takada T, Strasberg SM, et al. New diagnostic criteria and severity assessment of acute cholangitis in revised Tokyo guidelines. J Hepatobiliary Pancreat Sci. 2012;19(5):548-556.
3. Schneider J, Hapfelmeier A, Thöres S, et al. Mortality Risk for Acute Cholangitis (MAC): a risk prediction model for in-hospital mortality in patients with acute cholangitis. BMC Gastroenterol 2016;16:15.
4. Yamamoto K Gotoda T, Kusano C, Liu J, Yasuda T, Itoi T, Moriyasu F. Severe Acute Cholangitis with Complications of Bacterial Meningitis Associated with Hearing Loss. Intern Med. 2015;54(14):1757-1760.
5. Qin YS, Li QY, Yang FC, Zheng SS. Risk factors and incidence of acute pyogenic cholangitis. Hepatobiliary Pancreat Dis Int. 2012;11(6):650-654.
6. Kim SW, Shin HC, Kim HC, Hong MJ, Kim IY. Diagnostic performance of multidetector CT for acute cholangitis: evaluation of a CT scoring method. Br J Radiol. 2012;85(1014):770-777.
7. Longo DL, Fauci AS, Kasper DL, Hauser SL, Jameson J, Loscalzo J. eds. Harrison's Principles of Internal Medicine, 18e. New York, NY: McGraw-Hill; 2012.
8. Mandell GL, Bennett JE, Dolin R. Mandel, Douglas and Bennett's Principles and Practice of Infectious Diseases. 8th ed. Philadelphia, Pennsylvania: Churchill Livingstone; 2015.