Enteric Fever (Typhoid Fever) (Clinical)

Epidemiology and Etiology

Epidemiology^[2,3]

• Most prevalent in underdeveloped areas with poor sanitation Sanitation The development and establishment of environmental conditions favorable to the health of the public. Hepatitis E Virus
  • South-central and Southeast Asia ASIA Spinal Cord Injuries
  • Southern Africa
• World Health Organization (WHO) estimates (worldwide):
  • Incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency: 11–20 million cases/year
  • Deaths: 128,000–161,000 deaths/year
• The incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency in developed countries is low and almost always associated with travel to a high-risk area ( incidence Incidence The number of new cases of a given disease during a given period in a specified population. It also is used for the rate at which new events occur in a defined population. It is differentiated from prevalence, which refers to all cases in the population at a given time. Measures of Disease Frequency in the United States: 200–300 cases/year).

Etiology^[2,4]

• Causative agent: S. enterica serotype Typhi or Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella Typhi
  • Motile, encapsulated Encapsulated Klebsiella, Gram-negative bacilli Bacilli Shigella
  • Facultative intracellular Facultative intracellular Yersinia spp./Yersiniosis within macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation
  • Produces black colonies on Hektoen agar
  • Acid labile Acid labile Vibrio (requires a high inoculum) 
• Exam tip: While not commonly tested,  Salmonella Paratyphi Salmonella paratyphi A serotype of Salmonella enterica which is an agent of paratyphoid fever in humans. Salmonella serotypes A, B, and C can also cause enteric fever Enteric Fever Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) (paratyphoid fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever).

Pathophysiology

Transmission^[1,2,4,5]

• Fecal-oral transmission
  • Humans are the only reservoir Reservoir Animate or inanimate sources which normally harbor disease-causing organisms and thus serve as potential sources of disease outbreaks. Reservoirs are distinguished from vectors (disease vectors) and carriers, which are agents of disease transmission rather than continuing sources of potential disease outbreaks. Humans may serve both as disease reservoirs and carriers. Escherichia coli.
  • Chronic carriers Carriers The Cell: Cell Membrane have  gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract: Anatomy colonization Colonization Bacteriology (e.g., “ Typhoid Typhoid Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) Mary”).
• Severity of disease is dependent on:
  • Infecting species (S. Typhi versus S. Paratyphi)
  • Infectious dose Infectious dose Enteric Fever (Typhoid Fever) (high inoculum is required to survive exposure to gastric acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance)

Pathogenesis^[4]

After ingestion of  Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella Typhi:

• Bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology must survive exposure to gastric acids Acids Chemical compounds which yield hydrogen ions or protons when dissolved in water, whose hydrogen can be replaced by metals or basic radicals, or which react with bases to form salts and water (neutralization). An extension of the term includes substances dissolved in media other than water. Acid-Base Balance.
• Bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology adhere to and invade intestinal M cells M cells Salmonella of Peyer’s patches Patches Vitiligo.
• After invasion, the bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology replicate within macrophages Macrophages The relatively long-lived phagocytic cell of mammalian tissues that are derived from blood monocytes. Main types are peritoneal macrophages; alveolar macrophages; histiocytes; kupffer cells of the liver; and osteoclasts. They may further differentiate within chronic inflammatory lesions to epithelioid cells or may fuse to form foreign body giant cells or langhans giant cells. Innate Immunity: Phagocytes and Antigen Presentation in Peyer’s patches Patches Vitiligo, mesenteric lymph nodes Lymph Nodes They are oval or bean shaped bodies (1 – 30 mm in diameter) located along the lymphatic system. Lymphatic Drainage System: Anatomy, and the spleen Spleen The spleen is the largest lymphoid organ in the body, located in the LUQ of the abdomen, superior to the left kidney and posterior to the stomach at the level of the 9th-11th ribs just below the diaphragm. The spleen is highly vascular and acts as an important blood filter, cleansing the blood of pathogens and damaged erythrocytes. Spleen: Anatomy. This causes an inflammatory reaction with hypertrophy Hypertrophy General increase in bulk of a part or organ due to cell enlargement and accumulation of fluids and secretions, not due to tumor formation, nor to an increase in the number of cells (hyperplasia). Cellular Adaptation of Peyer’s patches Patches Vitiligo and recruitment Recruitment Skeletal Muscle Contraction of mononuclear cells and lymphocytes Lymphocytes Lymphocytes are heterogeneous WBCs involved in immune response. Lymphocytes develop from the bone marrow, starting from hematopoietic stem cells (HSCs) and progressing to common lymphoid progenitors (CLPs). B and T lymphocytes and natural killer (NK) cells arise from the lineage. Lymphocytes: Histology.
• Bacteria Bacteria Bacteria are prokaryotic single-celled microorganisms that are metabolically active and divide by binary fission. Some of these organisms play a significant role in the pathogenesis of diseases. Bacteriology spread hematogenously through the bloodstream and lymphatic system Lymphatic system A system of organs and tissues that process and transport immune cells and lymph. Primary Lymphatic Organs, causing:
  • Localized infection of the lymphoid tissue and small intestine Small intestine The small intestine is the longest part of the GI tract, extending from the pyloric orifice of the stomach to the ileocecal junction. The small intestine is the major organ responsible for chemical digestion and absorption of nutrients. It is divided into 3 segments: the duodenum, the jejunum, and the ileum. Small Intestine: Anatomy
  • Bacteremia Bacteremia The presence of viable bacteria circulating in the blood. Fever, chills, tachycardia, and tachypnea are common acute manifestations of bacteremia. The majority of cases are seen in already hospitalized patients, most of whom have underlying diseases or procedures which render their bloodstreams susceptible to invasion. Glycopeptides 

Clinical Presentation

Infection with S. Typhi results in typhoid Typhoid Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) (or enteric) fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever. Typhoid Typhoid Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever is a severe systemic illness associated with fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever (cardinal symptom) and abdominal pain Abdominal Pain Acute Abdomen.^[2,4,9,13]

• The incubation Incubation The amount time between exposure to an infectious agent and becoming symptomatic. Rabies Virus period is 5–21 days.
• In the pediatric age group:^[14]
  • Complications and hospitalization Hospitalization The confinement of a patient in a hospital. Delirium rate are higher in children < 5 years of age.
  • Infants have more risk of toxicity Toxicity Dosage Calculation and higher mortality Mortality All deaths reported in a given population. Measures of Health Status.

Diagnosis

Diagnosis is dependent on a high degree of suspicion as cultures are often negative, take many days, and may not be available in resource-poor areas. 

• Consider enteric fever Enteric Fever Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) in a febrile patient (with or without diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea) presenting with:^[8]
  • A history of travel to endemic areas
  • Consumption of foods prepared by people with recent endemic exposure
  • Laboratory exposure to Salmonella enterica Salmonella enterica A subgenus of Salmonella containing several medically important serotypes. The habitat for the majority of strains is warm-blooded animals. Salmonella serotypes Typhi and Paratyphi
• Confirmed by blood and stool cultures:^[6,19]
  • Blood cultures will be positive for Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella species in 50%–70% of cases.
    • Positive results decline after the 1st week.^[9] 
    • Preferred choice of the British Infection Association (BIA)^[9]
  • Stool cultures will be positive for Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella species in 30%–40% of cases.
• Bone marrow Bone marrow The soft tissue filling the cavities of bones. Bone marrow exists in two types, yellow and red. Yellow marrow is found in the large cavities of large bones and consists mostly of fat cells and a few primitive blood cells. Red marrow is a hematopoietic tissue and is the site of production of erythrocytes and granular leukocytes. Bone marrow is made up of a framework of connective tissue containing branching fibers with the frame being filled with marrow cells. Bone Marrow: Composition and Hematopoiesis culture:^[6,9]
  • Most sensitive (96%) diagnostic test (rarely indicated, but considered the gold standard)
  • Bacterial load is not affected by duration of symptoms.
  • May be of use if individual is nonresponsive to treatment to determine antibiotic resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing
• Other specimens that can be used (for culture):^[1,9]
  • Urine
  • Duodenal aspirate
• Serology Serology The study of serum, especially of antigen-antibody reactions in vitro. Yellow Fever Virus:^[1,7,9]
  • Widal test:
    • Used in developing countries (low cost)
    • Elevated antibody titers are detected, but acute infection cannot be distinguished from previous one.
  • Rapid antibody tests: suboptimal diagnostic accuracy
• If other risk factors (e.g., recent travel to a high-risk) are present, clinical diagnosis is possible based on:^[14]
  • Prolonged fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever (> 3 days)
  • Gastrointestinal (GI) symptoms
    • Abdominal pain Abdominal Pain Acute Abdomen
    • Diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea
    • Constipation Constipation Constipation is common and may be due to a variety of causes. Constipation is generally defined as bowel movement frequency < 3 times per week. Patients who are constipated often strain to pass hard stools. The condition is classified as primary (also known as idiopathic or functional constipation) or secondary, and as acute or chronic. Constipation
• Other laboratory findings:^[9]
  • Anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types
  • Elevated CRP
  • Elevated transaminases Transaminases A subclass of enzymes of the transferase class that catalyze the transfer of an amino group from a donor (generally an amino acid) to an acceptor (generally a 2-keto acid). Most of these enzymes are pyridoxyl phosphate proteins. Autoimmune Hepatitis
• Imaging:^[8]
  • Not required for diagnosis of infection
  • CT scan or MRI may be needed if there are signs of peritonitis Peritonitis Inflammation of the peritoneum lining the abdominal cavity as the result of infectious, autoimmune, or chemical processes. Primary peritonitis is due to infection of the peritoneal cavity via hematogenous or lymphatic spread and without intra-abdominal source. Secondary peritonitis arises from the abdominal cavity itself through rupture or abscess of intra-abdominal organs. Penetrating Abdominal Injury and/or indications of extraintestinal infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease.

Management and Prevention

Treatment options may vary based on practice location. The following information was gleaned from US and UK guidelines.

Treatment considerations 

• General management includes adequate hydration, antipyretic Antipyretic Acetaminophen therapy, and correction of electrolyte imbalances.
• In the United States, although most infections Infections Invasion of the host organism by microorganisms or their toxins or by parasites that can cause pathological conditions or diseases. Chronic Granulomatous Disease are acquired from other regions, treatment can be a challenge with the rise of multidrug-resistant (MDR) and extensively drug-resistant (XDR) organisms.^[10]
  • MDR typhoid Typhoid Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) is resistant to chloramphenicol Chloramphenicol Chloramphenicol, the only clinically relevant drug in the amphenicol class, is a potent inhibitor of bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing peptide bond formation. Chloramphenicol is a broad-spectrum antibiotic with wide distribution; however, due to its toxicity, its use is limited to severe infections. Chloramphenicol, ampicillin Ampicillin Semi-synthetic derivative of penicillin that functions as an orally active broad-spectrum antibiotic. Penicillins, and trimethoprim Trimethoprim The sulfonamides are a class of antimicrobial drugs inhibiting folic acid synthesize in pathogens. The prototypical drug in the class is sulfamethoxazole. Although not technically sulfonamides, trimethoprim, dapsone, and pyrimethamine are also important antimicrobial agents inhibiting folic acid synthesis. The agents are often combined with sulfonamides, resulting in a synergistic effect. Sulfonamides and Trimethoprim– sulfamethoxazole Sulfamethoxazole A bacteriostatic antibacterial agent that interferes with folic acid synthesis in susceptible bacteria. Its broad spectrum of activity has been limited by the development of resistance. Sulfonamides and Trimethoprim (TMP-SMX).^[15]
  • Fluoroquinolones Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones (with azithromycin Azithromycin A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. Macrolides and Ketolides and cephalosporins Cephalosporins Cephalosporins are a group of bactericidal beta-lactam antibiotics (similar to penicillins) that exert their effects by preventing bacteria from producing their cell walls, ultimately leading to cell death. Cephalosporins are categorized by generation and all drug names begin with “cef-” or “ceph-.” Cephalosporins) have become the major choices, but resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing has been noted in certain areas (e.g., South Asia ASIA Spinal Cord Injuries).^[12]
  • XDR typhoid Typhoid Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever):
    • Resistant to chloramphenicol Chloramphenicol Chloramphenicol, the only clinically relevant drug in the amphenicol class, is a potent inhibitor of bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing peptide bond formation. Chloramphenicol is a broad-spectrum antibiotic with wide distribution; however, due to its toxicity, its use is limited to severe infections. Chloramphenicol, ampicillin Ampicillin Semi-synthetic derivative of penicillin that functions as an orally active broad-spectrum antibiotic. Penicillins, TMP-SMX, fluoroquinolones Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones, and 3rd-generation cephalosporins Cephalosporins Cephalosporins are a group of bactericidal beta-lactam antibiotics (similar to penicillins) that exert their effects by preventing bacteria from producing their cell walls, ultimately leading to cell death. Cephalosporins are categorized by generation and all drug names begin with “cef-” or “ceph-.” Cephalosporins^[12]
    • Shows susceptibility to azithromycin Azithromycin A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. Macrolides and Ketolides and carbapenems Carbapenems A group of beta-lactam antibiotics in which the sulfur atom in the thiazolidine ring of the penicillin molecule is replaced by a carbon atom. Thienamycins are a subgroup of carbapenems which have a sulfur atom as the first constituent of the side chain. Carbapenems and Aztreonam^[20]
    • In endemic areas (especially Pakistan), the majority of the isolates are resistant to fluoroquinolones Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones.^[1,11,12]
    • There are ceftriaxone-resistant strains in Iraq as well.^[12]
• Treatment is directed by:
  • Illness severity:
    • Uncomplicated infection: no systemic symptoms, able to tolerate oral medication
    • Complicated infection: with systemic symptoms, organ dysfunction, altered mental status Altered Mental Status Sepsis in Children, requiring hospitalization Hospitalization The confinement of a patient in a hospital. Delirium
  • Patterns of drug resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing in the region where infection was acquired
• Report cases to local health officials/departments: Typhoid Typhoid Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever is a notifiable disease in the US and the UK.^[9,19]

Treatment for uncomplicated infection

1. Acquired in a region WITHOUT extensive drug resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing:^[1,8,14,15]
   • Fluoroquinolones Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones, such as ciprofloxacin Ciprofloxacin A broad-spectrum antimicrobial carboxyfluoroquinoline. Fluoroquinolones (oral):
     • In children, there is a risk of arthropathy Arthropathy Osteoarthritis and cartilage Cartilage Cartilage is a type of connective tissue derived from embryonic mesenchyme that is responsible for structural support, resilience, and the smoothness of physical actions. Perichondrium (connective tissue membrane surrounding cartilage) compensates for the absence of vasculature in cartilage by providing nutrition and support. Cartilage: Histology damage with fluoroquinolone intake.
     • BIA recommends against empiric use of fluoroquinolone without susceptibility studies.^[9]
   • Azithromycin Azithromycin A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. Macrolides and Ketolides (oral)
   • Cefixime (oral)
2. Acquired in a region WITH extensive drug resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing (e.g., Pakistan or Iraq): azithromycin Azithromycin A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. Macrolides and Ketolides^[1,9]

Treatment for complicated infection

• Acquired in a region WITHOUT extensive drug resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing:^[9,15,17]
  • Ceftriaxone Ceftriaxone A broad-spectrum cephalosporin antibiotic and cefotaxime derivative with a very long half-life and high penetrability to meninges, eyes and inner ears. Cephalosporins (1st choice):
    • Dose (adult): 2 g IV every 12‒24 hours for 10‒14 days
    • Dose (children): 50‒100 mg/kg IV in 1 or 2 divided doses (maximum: 4 g/day)
  • Cefotaxime Cefotaxime Semisynthetic broad-spectrum cephalosporin. Cephalosporins:
    • Dose (adult): 1‒2 g IV every 6‒8 hours for 10‒14 days
    • Dose (children): 150‒200 mg/kg IV per day in 3‒4 divided doses (maximum: 8 g per day)
  • Aztreonam Aztreonam The carbapenems and aztreonam are both members of the bactericidal beta-lactam family of antibiotics (similar to penicillins). They work by preventing bacteria from producing their cell wall, ultimately leading to bacterial cell death. Carbapenems and Aztreonam (in cephalosporin Cephalosporin Multidrug-resistant Organisms and Nosocomial Infections allergy Allergy An abnormal adaptive immune response that may or may not involve antigen-specific IgE Type I Hypersensitivity Reaction)
  • Fluoroquinolones Fluoroquinolones Fluoroquinolones are a group of broad-spectrum, bactericidal antibiotics inhibiting bacterial DNA replication. Fluoroquinolones cover gram-negative, anaerobic, and atypical organisms, as well as some gram-positive and multidrug-resistant (MDR) organisms. Fluoroquinolones are an option if resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing rate is low.
• Acquired in a region WITH extensive drug resistance Resistance Physiologically, the opposition to flow of air caused by the forces of friction. As a part of pulmonary function testing, it is the ratio of driving pressure to the rate of air flow. Ventilation: Mechanics of Breathing:^[9,18]
  • Meropenem Meropenem A thienamycin derivative antibacterial agent that is more stable to renal dehydropeptidase I than imipenem, but does not need to be given with an enzyme inhibitor such as cilastatin. It is used in the treatment of bacterial infections, including infections in immunocompromised patients. Carbapenems and Aztreonam:
    • Dose (adult): 1–2 g IV every 8 hours for 10‒14 days
    • Dose (children): 20‒40 mg/kg every 8 hours (maximum: 6000 mg/day)
  • Meropenem Meropenem A thienamycin derivative antibacterial agent that is more stable to renal dehydropeptidase I than imipenem, but does not need to be given with an enzyme inhibitor such as cilastatin. It is used in the treatment of bacterial infections, including infections in immunocompromised patients. Carbapenems and Aztreonam + azithromycin Azithromycin A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. Macrolides and Ketolides^[20]
• Transition to oral therapy when symptoms improve, basing the choice of antibiotics on susceptibility studies.
• Corticosteroids Corticosteroids Chorioretinitis:^[13,14]
  • Beneficial in severe enteric fever Enteric Fever Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) ( delirium Delirium Delirium is a medical condition characterized by acute disturbances in attention and awareness. Symptoms may fluctuate during the course of a day and involve memory deficits and disorientation. Delirium, coma Coma Coma is defined as a deep state of unarousable unresponsiveness, characterized by a score of 3 points on the GCS. A comatose state can be caused by a multitude of conditions, making the precise epidemiology and prognosis of coma difficult to determine. Coma, or shock Shock Shock is a life-threatening condition associated with impaired circulation that results in tissue hypoxia. The different types of shock are based on the underlying cause: distributive (↑ cardiac output (CO), ↓ systemic vascular resistance (SVR)), cardiogenic (↓ CO, ↑ SVR), hypovolemic (↓ CO, ↑ SVR), obstructive (↓ CO), and mixed. Types of Shock)
  • Dexamethasone Dexamethasone An anti-inflammatory 9-fluoro-glucocorticoid. Antiemetics: initial dose of 3 mg/kg, then 1 mg/kg every 6 hours for 48 hours
  • Administer in a monitored setting, as abdominal symptoms may be masked.
• Surgical management is required for ileal perforation Perforation A pathological hole in an organ, blood vessel or other soft part of the body, occurring in the absence of external force. Esophagitis.

Prevention

• Two vaccines are available for those traveling to high-risk areas:^[5,14,15]
  • Intramuscular, inactivated vaccine Vaccine Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa), antigenic proteins, synthetic constructs, or other bio-molecular derivatives, administered for the prevention, amelioration, or treatment of infectious and other diseases. Vaccination (Vi polysaccharide vaccine Vaccine Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa), antigenic proteins, synthetic constructs, or other bio-molecular derivatives, administered for the prevention, amelioration, or treatment of infectious and other diseases. Vaccination):
    • Contains capsular polysaccharide
    • Must be > 2 years old
    • Booster may be needed every 2 years for continued protection.
  • Oral, live-attenuated vaccine Vaccine Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa), antigenic proteins, synthetic constructs, or other bio-molecular derivatives, administered for the prevention, amelioration, or treatment of infectious and other diseases. Vaccination (Ty21a vaccine Vaccine Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa), antigenic proteins, synthetic constructs, or other bio-molecular derivatives, administered for the prevention, amelioration, or treatment of infectious and other diseases. Vaccination):
    • Capsules taken on alternate days for 4 doses.
    • Contraindicated in pregnant women, children < age of 6 years, and immunocompromised immunocompromised A human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation. Gastroenteritis patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
    • Requires booster (every 5 years) if continued protection is needed
• Vaccine Vaccine Suspensions of killed or attenuated microorganisms (bacteria, viruses, fungi, protozoa), antigenic proteins, synthetic constructs, or other bio-molecular derivatives, administered for the prevention, amelioration, or treatment of infectious and other diseases. Vaccination not available in Europe or US (Vi typhoid Typhoid Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) conjugate vaccines):^[1,5]
  • 1 IM dose (booster need uncertain)
  • Better efficacy in patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship < 2 years of age
• Hand hygiene Hand hygiene Practices involved in preventing the transmission of diseases by hand. Surgical Infections, food, and water safety are also key.
• Any infected individual must avoid preparing food for others.

Complications

• Complications of typhoid Typhoid Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) are typically associated with untreated infection in the 3rd phase (or week) of infection. The most common complications include:^[1,9]
  • GI bleeding
  • Ileal perforation Perforation A pathological hole in an organ, blood vessel or other soft part of the body, occurring in the absence of external force. Esophagitis
  • Encephalopathy Encephalopathy Hyper-IgM Syndrome
  • Myocarditis Myocarditis Myocarditis is an inflammatory disease of the myocardium, which may occur alone or in association with a systemic process. There are numerous etiologies of myocarditis, but all lead to inflammation and myocyte injury, most often leading to signs and symptoms of heart failure. Myocarditis, rarely pericarditis Pericarditis Pericarditis is an inflammation of the pericardium, often with fluid accumulation. It can be caused by infection (often viral), myocardial infarction, drugs, malignancies, metabolic disorders, autoimmune disorders, or trauma. Acute, subacute, and chronic forms exist. Pericarditis
  • Visceral abscesses
  • Osteomyelitis Osteomyelitis Osteomyelitis is an infection of the bone that results from the spread of microorganisms from the blood (hematogenous), nearby infected tissue, or open wounds (non-hematogenous). Infections are most commonly caused by Staphylococcus aureus. Osteomyelitis
  • Overwhelming sepsis Sepsis Systemic inflammatory response syndrome with a proven or suspected infectious etiology. When sepsis is associated with organ dysfunction distant from the site of infection, it is called severe sepsis. When sepsis is accompanied by hypotension despite adequate fluid infusion, it is called septic shock. Sepsis and Septic Shock
• Another complication, usually associated with asymptomatic infection, is developing a chronic carrier Carrier Vaccination state:^[1,5,9]
  • Positive Salmonella Salmonella Salmonellae are gram-negative bacilli of the family Enterobacteriaceae. Salmonellae are flagellated, non-lactose-fermenting, and hydrogen sulfide-producing microbes. Salmonella enterica, the most common disease-causing species in humans, is further classified based on serotype as typhoidal (S. typhi and paratyphi) and nontyphoidal (S. enteritidis and typhimurium). Salmonella in stool or urine cultures > 1 year after acute infection
    • More frequent in adult women and patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship with cholelithiasis Cholelithiasis Cholelithiasis (gallstones) is the presence of stones in the gallbladder. Most gallstones are cholesterol stones, while the rest are composed of bilirubin (pigment stones) and other mixed components. Patients are commonly asymptomatic but may present with biliary colic (intermittent pain in the right upper quadrant). Cholelithiasis or other biliary tract Biliary tract Bile is secreted by hepatocytes into thin channels called canaliculi. These canaliculi lead into slightly larger interlobular bile ductules, which are part of the portal triads at the “corners” of hepatic lobules. The bile leaves the liver via the right and left hepatic ducts, which join together to form the common hepatic duct. Gallbladder and Biliary Tract: Anatomy abnormalities
    • Occurs in up to 6% of patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship
    • Treatment: ciprofloxacin Ciprofloxacin A broad-spectrum antimicrobial carboxyfluoroquinoline. Fluoroquinolones (500‒750 mg/day) for at least 1 month
    • BIA also recommends azithromycin Azithromycin A semi-synthetic macrolide antibiotic structurally related to erythromycin. It has been used in the treatment of Mycobacterium avium intracellulare infections, toxoplasmosis, and cryptosporidiosis. Macrolides and Ketolides or amoxicillin Amoxicillin A broad-spectrum semisynthetic antibiotic similar to ampicillin except that its resistance to gastric acid permits higher serum levels with oral administration. Penicillins as an option.
    • Cholecystectomy Cholecystectomy Cholecystectomy is a surgical procedure performed with the goal of resecting and extracting the gallbladder. It is one of the most common abdominal surgeries performed in the Western world. Cholecystectomy is performed for symptomatic cholelithiasis, cholecystitis, gallbladder polyps > 0.5 cm, porcelain gallbladder, choledocholithiasis and gallstone pancreatitis, and rarely, for gallbladder cancer. Cholecystectomy is an option if antimicrobial therapy fails.
  • Associated with an increased risk of carcinoma of the gallbladder Gallbladder The gallbladder is a pear-shaped sac, located directly beneath the liver, that sits on top of the superior part of the duodenum. The primary functions of the gallbladder include concentrating and storing up to 50 mL of bile. Gallbladder and Biliary Tract: Anatomy
  • Patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship must avoid working in the food industry.
• Relapse Relapse Relapsing Fever can occur after treatment, and is usually noted 2‒3 weeks after fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever resolution.^[5]
  • Noted in chloramphenicol Chloramphenicol Chloramphenicol, the only clinically relevant drug in the amphenicol class, is a potent inhibitor of bacterial protein synthesis by binding to the 50S ribosomal subunit and preventing peptide bond formation. Chloramphenicol is a broad-spectrum antibiotic with wide distribution; however, due to its toxicity, its use is limited to severe infections. Chloramphenicol use (an older antibiotic)
  • Less relapse Relapse Relapsing Fever noted with the new antibiotics

Differential Diagnosis

• Amebic liver Liver The liver is the largest gland in the human body. The liver is found in the superior right quadrant of the abdomen and weighs approximately 1.5 kilograms. Its main functions are detoxification, metabolism, nutrient storage (e.g., iron and vitamins), synthesis of coagulation factors, formation of bile, filtration, and storage of blood. Liver: Anatomy/hepatic abscess Abscess Accumulation of purulent material in tissues, organs, or circumscribed spaces, usually associated with signs of infection. Chronic Granulomatous Disease:
  • Most common extraintestinal manifestation of amebiasis Amebiasis Amebiasis, or amoebic dysentery, is an infection caused by the parasite Entamoeba histolytica. Transmission is through the fecal-oral route or by consumption of contaminated food and water. Most patients infected with E. histolytica are asymptomatic, but about 10% may develop dysentery. Entamoeba spp./Amebiasis
  • As with typhoid Typhoid Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, may present with pulmonary, cardiac, and central nervous system Central nervous system The main information-processing organs of the nervous system, consisting of the brain, spinal cord, and meninges. Nervous System: Anatomy, Structure, and Classification (CNS) manifestations
  • Different fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever pattern
  • No rose-colored papular rash Rash Rocky Mountain Spotted Fever
• Appendicitis Appendicitis Appendicitis is the acute inflammation of the vermiform appendix and the most common abdominal surgical emergency globally. The condition has a lifetime risk of 8%. Characteristic features include periumbilical abdominal pain that migrates to the right lower quadrant, fever, anorexia, nausea, and vomiting. Appendicitis:
  • As with typhoid Typhoid Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, may present with abdominal pain Abdominal Pain Acute Abdomen and fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Abdominal pain Abdominal Pain Acute Abdomen is localized to the right lower quadrant Right lower quadrant Anterior Abdominal Wall: Anatomy
• Toxoplasmosis Toxoplasmosis Toxoplasmosis is an infectious disease caused by Toxoplasma gondii, an obligate intracellular protozoan parasite. Felines are the definitive host, but transmission to humans can occur through contact with cat feces or the consumption of contaminated foods. The clinical presentation and complications depend on the host’s immune status. Toxoplasma/Toxoplasmosis:
  • As with typhoid Typhoid Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, may present with headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, sore throat Sore throat Pharyngitis is an inflammation of the back of the throat (pharynx). Pharyngitis is usually caused by an upper respiratory tract infection, which is viral in most cases. It typically results in a sore throat and fever. Other symptoms may include a runny nose, cough, headache, and hoarseness. Pharyngitis, malaise Malaise Tick-borne Encephalitis Virus, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus, and neurological symptoms
  • History of exposure to cats
  • Immunocompromised immunocompromised A human or animal whose immunologic mechanism is deficient because of an immunodeficiency disorder or other disease or as the result of the administration of immunosuppressive drugs or radiation. Gastroenteritis patients Patients Individuals participating in the health care system for the purpose of receiving therapeutic, diagnostic, or preventive procedures. Clinician–Patient Relationship will have brain Brain The part of central nervous system that is contained within the skull (cranium). Arising from the neural tube, the embryonic brain is comprised of three major parts including prosencephalon (the forebrain); mesencephalon (the midbrain); and rhombencephalon (the hindbrain). The developed brain consists of cerebrum; cerebellum; and other structures in the brain stem. Nervous System: Anatomy, Structure, and Classification abscesses with multiple ring-enhancing lesions on magnetic resonance imaging (MRI).
• Tuberculosis Tuberculosis Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis ( TB TB Tuberculosis (TB) is an infectious disease caused by Mycobacterium tuberculosis complex bacteria. The bacteria usually attack the lungs but can also damage other parts of the body. Approximately 30% of people around the world are infected with this pathogen, with the majority harboring a latent infection. Tuberculosis spreads through the air when a person with active pulmonary infection coughs or sneezes. Tuberculosis):
  • As with typhoid Typhoid Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, may present with  abdominal pain Abdominal Pain Acute Abdomen, vomiting Vomiting The forcible expulsion of the contents of the stomach through the mouth. Hypokalemia, diarrhea Diarrhea Diarrhea is defined as ≥ 3 watery or loose stools in a 24-hour period. There are a multitude of etiologies, which can be classified based on the underlying mechanism of disease. The duration of symptoms (acute or chronic) and characteristics of the stools (e.g., watery, bloody, steatorrheic, mucoid) can help guide further diagnostic evaluation. Diarrhea, malaise Malaise Tick-borne Encephalitis Virus, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, and weight loss Weight loss Decrease in existing body weight. Bariatric Surgery
  • Infection is typically localized to the lungs Lungs Lungs are the main organs of the respiratory system. Lungs are paired viscera located in the thoracic cavity and are composed of spongy tissue. The primary function of the lungs is to oxygenate blood and eliminate CO2. Lungs: Anatomy with chest X-ray X-ray Penetrating electromagnetic radiation emitted when the inner orbital electrons of an atom are excited and release radiant energy. X-ray wavelengths range from 1 pm to 10 nm. Hard x-rays are the higher energy, shorter wavelength x-rays. Soft x-rays or grenz rays are less energetic and longer in wavelength. The short wavelength end of the x-ray spectrum overlaps the gamma rays wavelength range. The distinction between gamma rays and x-rays is based on their radiation source. Pulmonary Function Tests showing cavitations and mediastinal or hilar lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy. 
• Leishmaniasis Leishmaniasis Leishmania species are obligate intracellular parasites that are transmitted by an infected sandfly. The mildest form is cutaneous leishmaniasis (CL), characterized by painless skin ulcers. The mucocutaneous type involves more tissue destruction, causing deformities. Visceral leishmaniasis (VL), the most severe form, presents with hepatosplenomegaly, anemia, thrombocytopenia, and fever. Leishmania/Leishmaniasis:
  • As with typhoid Typhoid Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, may present with hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, anemia Anemia Anemia is a condition in which individuals have low Hb levels, which can arise from various causes. Anemia is accompanied by a reduced number of RBCs and may manifest with fatigue, shortness of breath, pallor, and weakness. Subtypes are classified by the size of RBCs, chronicity, and etiology. Anemia: Overview and Types, and anorexia Anorexia The lack or loss of appetite accompanied by an aversion to food and the inability to eat. It is the defining characteristic of the disorder anorexia nervosa. Anorexia Nervosa
  • Either skin Skin The skin, also referred to as the integumentary system, is the largest organ of the body. The skin is primarily composed of the epidermis (outer layer) and dermis (deep layer). The epidermis is primarily composed of keratinocytes that undergo rapid turnover, while the dermis contains dense layers of connective tissue. Skin: Structure and Functions ulcerations or a clinical history of spiking fevers, hepatosplenomegaly Hepatosplenomegaly Cytomegalovirus, and pancytopenia Pancytopenia Deficiency of all three cell elements of the blood, erythrocytes, leukocytes and platelets. Aplastic Anemia with exposure to sandflies
• Brucellosis Brucellosis Brucellosis (also known as undulant fever, Mediterranean fever, or Malta fever) is a zoonotic infection that spreads predominantly through ingestion of unpasteurized dairy products or direct contact with infected animal products. Clinical manifestations include fever, arthralgias, malaise, lymphadenopathy, and hepatosplenomegaly. Brucella/Brucellosis:
  • As with typhoid Typhoid Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, may present with malaise Malaise Tick-borne Encephalitis Virus, fatigue Fatigue The state of weariness following a period of exertion, mental or physical, characterized by a decreased capacity for work and reduced efficiency to respond to stimuli. Fibromyalgia, fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, lymphadenopathy Lymphadenopathy Lymphadenopathy is lymph node enlargement (> 1 cm) and is benign and self-limited in most patients. Etiologies include malignancy, infection, and autoimmune disorders, as well as iatrogenic causes such as the use of certain medications. Generalized lymphadenopathy often indicates underlying systemic disease. Lymphadenopathy, and myocarditis Myocarditis Myocarditis is an inflammatory disease of the myocardium, which may occur alone or in association with a systemic process. There are numerous etiologies of myocarditis, but all lead to inflammation and myocyte injury, most often leading to signs and symptoms of heart failure. Myocarditis
  • History of ingesting raw or unpasteurized dairy products or direct contact with infected animals Animals Unicellular or multicellular, heterotrophic organisms, that have sensation and the power of voluntary movement. Under the older five kingdom paradigm, animalia was one of the kingdoms. Under the modern three domain model, animalia represents one of the many groups in the domain eukaryota. Cell Types: Eukaryotic versus Prokaryotic (goats, sheep, pigs, etc ETC The electron transport chain (ETC) sends electrons through a series of proteins, which generate an electrochemical proton gradient that produces energy in the form of adenosine triphosphate (ATP). Electron Transport Chain (ETC).)
• Malaria Malaria Malaria is an infectious parasitic disease affecting humans and other animals. Most commonly transmitted via the bite of a female Anopheles mosquito infected with microorganisms of the Plasmodium genus. Patients present with fever, chills, myalgia, headache, and diaphoresis. Plasmodium/Malaria: 
  • As with typhoid Typhoid Typhoid (or enteric) fever is a severe, systemic bacterial infection classically caused by the facultative intracellular and Gram-negative bacilli Salmonella enterica serotype Typhi (S. Typhimurium, formerly S. typhi). S. paratyphi serotypes A, B, or C can cause a similar syndrome. Enteric Fever (Typhoid Fever) fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever, may present with headache Headache The symptom of pain in the cranial region. It may be an isolated benign occurrence or manifestation of a wide variety of headache disorders. Brain Abscess, malaise Malaise Tick-borne Encephalitis Virus, abdominal pain Abdominal Pain Acute Abdomen, paroxysmal high fever Fever Fever is defined as a measured body temperature of at least 38°C (100.4°F). Fever is caused by circulating endogenous and/or exogenous pyrogens that increase levels of prostaglandin E2 in the hypothalamus. Fever is commonly associated with chills, rigors, sweating, and flushing of the skin. Fever
  • Associated with travel history to an endemic region
  • Peripheral blood smear Peripheral Blood Smear Anemia: Overview and Types showing schizonts Schizonts Multinucleate cells or a stage in the development of sporozoan protozoa. It is exemplified by the life cycle of Plasmodium falciparum in the malaria infection cycle. Plasmodium/Malaria, hemolytic anemia Hemolytic Anemia Hemolytic anemia (HA) is the term given to a large group of anemias that are caused by the premature destruction/hemolysis of circulating red blood cells (RBCs). Hemolysis can occur within (intravascular hemolysis) or outside the blood vessels (extravascular hemolysis). Hemolytic Anemia, and thrombocytopenia Thrombocytopenia Thrombocytopenia occurs when the platelet count is < 150,000 per microliter. The normal range for platelets is usually 150,000-450,000/µL of whole blood. Thrombocytopenia can be a result of decreased production, increased destruction, or splenic sequestration of platelets. Patients are often asymptomatic until platelet counts are < 50,000/µL. Thrombocytopenia