Fever, infectious disease and sepsis

Fever, infectious disease and sepsis

The thermoregulatory center in the anterior hypothalamus balances heat production from metabolic activity in muscle and liver with heat loss from the skin and lungs to maintain a normal body temperature of 36.8° ± 0.4°C (98.2°± 0.7°F), with diurnal variation (lower in the morning, higher in the evening).
Fever is one of the most common signs of disease and accounts for

numerous adult and pediatric visits to the emergency department.  Fever is an elevated body temperature: An oral temperature > 37.8 °C  or a rectal temperature > 38°C .

The difference between fever and hyperthermia: 

The site that controls body temperature, i.e. the thermoregulatory center in the hypothalamus has an inherent set point (target temperature) of about 37°C This setpoint ranges from 36° to 37.8°C, affected by the normal daily circadian rhythm. The temperature is lowest around 4 AM and gradually increases during the day, reaching a peak between 6 and 10 PM.

Fever is present when the body's thermostat in the anterior hypothalamus, responding to a disease (usually an infection) resets the target body temperature at a higher level. Pyrogens are substances that cause an elevation of body temperature. Exogenous pyrogens are microorganisms or substances present in microorganisms (e.g the lipopolysaccharide of gram-negative bacteria) , or antigens. Such exogenous pyrogens induce the release of endogenous pyrogens. Endogenous pyrogens such as interleukin-1 (IL-1), interleukin 6, tumor necrosis factor-alpha (TNFa), etc. are cytokines produced by leucocytes and macrophages. Cytokines induce upward displacement of the set point of the thermoregulatory center, via the synthesis of prostaglandin E2.
Hyperthermia is an elevated body temperature that does not result from a resetting of the temperature setpoint by the anterior hypothalamus. The body attempts to maintain the normal temperature but the homeostatic mechanisms, such as vasodilation or increase in the production of sweat, for various reasons are not sufficient to effectively reduce the temperature of the body.
Extreme temperatures >41°C (106°F) almost always are a feature of hyperthermia and not a true fever.
Fever of unknown origin (FUO) is documented fever (38.3°C=101°F or higher temperature) that persists for 2-3 weeks without a diagnosis of the underlying cause despite reasonable investigation (usual definitions set a requirement of at least three outpatient visits or 3-7 days in inpatient care without a diagnosis of the cause).

Pathophysiology of fever

The site of body temperature regulation is the preoptic area of the anterior hypothalamus. This area continuously regulates the balance between heat production and heat loss.

Heat production is controlled by the following mechanisms:

 ►Regulation of the level of circulating thyroxin, the hormone of the thyroid gland. Thyroxin increases cellular metabolism and this results in increased heat production. 

►Increasing muscle activity (shivering when the environment is cold or the shaking chill occurring with fever) is a fast and effective mechanism of heat production
►Regulation of heat production by the hepatic metabolism

Heat loss is regulated by:

►The regulation of the volume of blood that flows to the skin’s surface through vasoconstriction which decreases heat loss and vasodilation, having the opposite effect.

►The amount of sweat production by the exocrine sweat glands. The vaporization of sweat results in cooling the body.

Etiology (causes) of fever 

Disorders causing fever are broadly categorized as : 

►Infectious disease 

(The most common cause of fever is an infection, with viral and bacterial upper and lower respiratory tract or gastrointestinal infections being the most common, followed by urinary tract infection). The list of all possible infectious causes is very extensive. 

►Neoplastic disease (Hodgkin's lymphoma, leukemia, colon cancer, renal adenocarcinoma, cardiac myxoma)

►Inflammatory non-infectious disease 
Collagen or rheumatic diseases and other inflammatory diseases such as systemic lupus erythematosus, Still's disease, Behcet's disease, Crohn's disease, gout, postcardiotomy syndrome
Vasculitis syndromes such as temporal arteritis, polyarteritis nodosa, polymyalgia rheumatica.
Granulomatous disorders such as sarcoidosis,
Transfusion reaction 
Drug-related fever 
Amphotericin B, beta-lactams (penicillins, cephalosporins), sulfonamides, carbamazepine, phenytoin, procainamide, quinidine, hydralazine, interferon-alpha, interleukin-2.
.►Tissue damage (e.g postoperative fever, myocardial infarction, hematoma)

►Thromboembolism (acute thrombophlebitis, pulmonary embolism)
►Neurologic causes 
(intracranial hemorrhage, cerebrovascular accident, malignant neuroleptic syndrome).
►Endocrine causes (thyroid storm)

Causes of fever to be treated in an emergency basis

The physician should be alert to quickly diagnose and treat any of the following causes of fever, which may pose significant risks to the patient and are generally considered as emergencies or as serious diseases.

Systemic conditions: 

sepsis-septic shock (see the chapter on shock Shock: diagnosis and treatment)

menigococcemia

From the central nervous system

meningitis (for its diagnosis and treatment click Meningitis)

encephalitis

cavernous sinus thrombosis

 brain abscess

From the respiratory system

pneumonia (which may in some cases cause respiratory failure), 

(For pneumonia diagnosis and treatment click Pneumonia )

epiglottitis

peritonsillar abscess

retropharyngeal abscess

From the cardiovascular system

infective endocarditis

pericarditis 

From the gastrointestinal system

peritonitis 

cholecystitis

appendicitis

diverticulitis

intra-abdominal abscess

From the genitourinary system

pyelonephritis

 tubo-ovarian abscess

pelvic inflammatory disease

From the skin and soft tissues

cellulitis,

 infected decubitus ulcer

 soft tissue abscess

From the skeletal system

osteomyelitis

The history of the patient with fever

It is important to determine if there are any associated symptoms and also if the onset of fever occurred in the hospital (suggestive of a nosocomial infection) or in the community. Associated symptoms can point toward the probable causes and guide subsequent diagnostic tests if necessary. The symptoms to ascertain include chills, rigors, night sweats, rash, arthralgias, myalgias, sore throat, cough, sputum production, postnasal drainage, dysuria (painful urination), urinary frequency (more frequent urination than normal e.g. every 1-2 hours), headache, facial pain, chest pain, abdominal pain, nausea, vomiting, diarrhea, pain at an intravenous site, and change in mental status. A rigor (shaking chill), suggests a bacterial infection (e.g. pneumonia, pyelonephritis, bacteremia, or sepsis ).

The history of any medical illnesses and surgeries, as well as any medications that the patient regularly takes,  is important. Information should be obtained whether a condition that can reduce the function of the patient's immune system is present because such conditions predispose to infections with certain microorganisms. For example, a history of splenectomy (usually due to splenic rupture as a result of trauma) carries a higher risk of infection with encapsulated microorganisms such as Streptococcus pneumoniae. An underlying malignancy, chemotherapy, other immunosuppressive medications (such as prednisone or azathioprine), or neutropenia, or AIDS (acquired immunodeficiency syndrome due to HIV virus infection) also place the patient at increased risk of infection and often with less common causal microorganisms (opportunistic infection).

There are also other conditions from the medical history which are important because they may predispose to specific infections, e.g. a prosthetic heart valve or a congenital heart defect can predispose to endocarditis, chronic obstructive pulmonary disease (COPD) which is usually the result of heavy smoking may predispose to a lower respiratory tract infection, renal calculi, anatomical or functional abnormalities of the urinary tract or pregnancy may predispose to pyelonephritis, patients with cholelithiasis or obese middle-aged or older females are at a higher risk for cholecystitis, chronic liver disease predisposes to spontaneous bacterial peritonitis, pneumococcal pneumonia or bacteremia, etc.
It is also important to consider if iatrogenic predisposing factors or causes of infection are present e.g. peripheral or central intravenous catheters can become infected, a nasogastric tube may predispose to sinusitis. a Foley catheter can predispose to a urinary tract infection, devices such as pacemakers and their leads can be infected, endotracheal intubation may predispose to a pulmonary infection, recent surgery can be complicated by infection of the wound, or infection of a prosthetic material recently placed, etc.

Physical examination of the patient with fever

 General appearance: Does the patient appear toxic, in a severe condition, or does he or she look relatively well? This can help decide whether the patient should be treated with empiric antibiotic therapy, before definitive diagnosis, based on the most likely cause.
A rigor (shaking chill), suggests a bacterial infection (e.g. pneumonia, pyelonephritis, bacteremia, or sepsis ). Vital signs: 
Oral and rectal temperature should be taken. (Known neutropenia is a contraindication to taking rectal temperature).
Pulse and blood pressure: It is very important to know if the patient is hemodynamically stable. Hypotension (systolic blood pressure < 100 mmHg) suggests sepsis or volume depletion.
As a general rule, the heart rate of a febrile patient is expected to be elevated, depending on body temperature.
If the heart rate is not elevated as expected by the level of fever (pulse-temperature dissociation), this may result from beta-blocker treatment or from certain specific causes of fever such as brucellosis, typhoid fever (Salmonella typhi), atypical pneumonia (pulmonary infection from Mycoplasma or Chlamydia pneumoniae or Legionella pneumophila), Psittacosis (infection by Chlamydia psittaci), malaria, drug-related fever, lymphoma, or fever due to central nervous system disorder. 
 Examination of the skin and inspection of the patient:
 Check for an area of focal erythema (suggesting an infection of the skin) or focal edema and erythema at sites of intravenous catheters, if any. In febrile patients with any type of catheter (e.g. an intravenous catheter or a Foley catheter) assume that fever is due to a catheter-related infection unless proved otherwise. Inspect the skin for rashes (in some cases the specific appearance of the rash may suggest the diagnosis). Pustules can be found in staphylococcal disease and gonococcemia. (Pustules are small circumscribed elevations of the skin containing pus and having an inflamed base).
Look for signs that may suggest infective endocarditis such as painful erythematous subcutaneous nodules on the tips of digits (Osler nodes), non-tender hemorrhagic macules on the palms or soles (Janeway lesions), petechiae, and splinter hemorrhages under the nails.

Purpuric rash of meningococcemia (bacteremia caused by fulminant infection by Neisseria Meningitidis) in a 15 year old girl . The girl was succesfully treated with intravenous ceftriaxone.Figure available via creative commons licence CC BY-NC 4.0 From Researchgate.net LINK  https://www.researchgate.net/figure/Purpuric-rash-of-meningococcemia-at-presentationReprinted-with-permission-from-The_fig1_255959317  From the article : Shrestha P, Shrestha NK, Giri S.  Rapid recovery following fulminant meningococcemia complicated by myocarditis in a 15-year-old Nepalese girl: a case report. International medical case reports journal. 2013 6. 33-6. 10.2147/IMCRJ.S36713. https://www.dovepress.com/rapid-recovery-following-fulminant-meningococcemia-complicated-by-myoc-peer-reviewed-article-IMCRJ

HEENT examination
Check for evidence of bacterial tonsilitis (red swollen tonsils with white spots and swollen uvula). In viral pharyngitis /tonsilitis tonsils will also be red and swollen but without white spots of pus and without a swollen uvula. Percuss the teeth for tenderness (suggesting an abscess). Percuss the paranasal sinuses for tenderness, suggestive of sinusitis. Examine the tympanic membranes with an otoscope for evidence of otitis media.
Lymph nodes
Check for enlarged lymph nodes (cervical, supraclavicular, epitrochlear, axillary, and inguinal nodes). In adults, nodes larger than 1 cm in diameter are often pathologic. Focal adenopathy may suggest the location of a bacterial infection in a territory drained by the affected lymph nodes, e.g. group A streptococcal pharyngitis classically can cause anterior cervical lymphadenopathy(with fever and a sore throat), whereas an infection of the hand may cause axillary lymphadenopathy. Note that most children normally have palpable anterior cervical, inguinal, and axillary lymph nodes that, if evaluated by adult standards, would be characterized as lymphadenopathy. Lymphoid mass gradually increases after birth until the age of 8-11 years and then it undergoes progressive atrophy during puberty. In young children, anterior cervical lymph nodes as large as 2 cm, inguinal lymph nodes as large as 1.5 cm and axillary nodes as large as 1 cm in diameter, are usually normal.

Diagnostic tests

Diagnostic tests are an adjunct to the history and the physical examination and they are selected according to the history and the findings of the physical examination.
Complete blood count (CBC)
An elevated number of white blood cells (WBC) is often associated with infection, though some viral infections are associated with
leukopenia (a reduced number of WBC). Bacterial infections are usually associated with an increase in polymorphonuclear neutrophils, often with an elevated number of earlier developmental forms such as bands. Viral infections usually demonstrate an increase in lymphocytes. Infections from some parasites demonstrate an increase in eosinophils.
Inflammatory Markers
The erythrocyte sedimentation rate (ESR) and the C-reactive protein (CRP) level rise in inflammation and they are used to assess a patient's level (severity/intensity) of inflammation. They are sensitive markers of inflammation but they are nonspecific tests regarding the cause and site of inflammation. CRP changes more rapidly in response to changes in the intensity of the inflammatory process (even in 24 hours) whereas  ESR changes slowly (in several days) therefore it is usually not useful to measure it more often than weekly.
Based on clinical suspicion serologic and antigen tests for specific pathogens can be ordered.
Cultures:
 For the diagnosis of infectious disease and for the identification of the microorganism and its sensitivity to drug treatment cultures are very helpful. Cultures involve the culture of fluid (e.g., blood, urine, sputum, pus from a wound) or the culture of infected
tissue (e.g., surgical specimens). Samples can be sent for culture of bacteria (aerobic or anaerobic), fungi, or viruses.
Analysis of cerebrospinal fluid (CSF) is indicated in patients with suspected meningitis or encephalitis.

Sepsis

Sepsis is a clinical syndrome that occurs in patients with infection (known or suspected) having indications of a systemic inflammatory response. According to a more recent task force definition sepsis is a clinical syndrome characterized by the presence of a life-threatening organ dysfunction caused by a dysregulated host response to infection.  Sepsis is a life-threatening condition, therefore early diagnosis is required and prompt treatment with intravenous empirical antibiotics.
 Sepsis can be defined as an infection that fulfills  two or more criteria of the systemic inflammatory response syndrome (SIRS), These criteria include:

• Fever or hypothermia (temperature  >38° C (>100.4 °F)  or < 36° C ( < 96.8°F)
• Resting respiratory rate >20/ minute (tachypnea)
• Resting heart rate (HR) >90 beats per minute (bpm)
• Altered mental status
• White blood cell count (WBC) elevated >12,000 or reduced <4,000 / or 10% bands
• Hyperglycemia (in a nondiabetic patient)

However, the SIRS criteria although sensitive to detect sepsis had a relatively low specificity since similar inflammatory responses can be seen as a response to non-infectious conditions (for example surgery, pancreatitis, etc). Furthermore, the SIRS criteria do not perform well in identifying patients with significant morbidity and mortality who need intensive treatment, probably in an ICU (intensive care unit).
These issues have led to a recent new consensus definition for sepsis in 2016. The international task force defined sepsis as a life-threatening organ dysfunction caused by a dysregulated host response to infection.

Patients with sepsis can also be identified using the qSOFA score which was developed by an international task force. A patient suspected to have an infection that fulfills two of the following criteria should be treated as a patient with sepsis:
qSOFA criteria

•  Respiratory rate ≥22/min
•  Glasgow Coma Scale <15
•  Systolic blood pressure ≤100 mmHg

Severe sepsis is a clinical syndrome of sepsis that is associated with at least one new organ dysfunction. The presence of at least one of the following findings in a patient with sepsis is indicative of severe sepsis:

• Systolic blood pressure (SBP) <90 mmHg or mean arterial pressure (MAP) <60 mmHg, 
• Change in mental status, delirium
• Indications of reduced peripheral tissue perfusion, such as  poor extremity perfusion (cool extremities, livedo reticularis) or lactic acidosis (2.0–4.0 mM/L) (mM/L= millimole per liter)
• New renal dysfunction: Increased creatinine (>2.0 mg/dl or increase in creatinine by 50%) or oliguria
• New respiratory dysfunction: Hypoxia or high FiO2 requirement
• Abnormal prothrombin time/partial thromboplastin time (PT/PTT) or low platelets (<100,000)
• New hepatic dysfunction: Hyperbilirubinemia (>2.0 mg/dl) or liver function tests > twice the upper limit of normal

Septic shock is a subcategory of severe sepsis characterized by severe circulatory dysfunction due to an infection, as defined by hypotension (systolic BP <90 mmHg or 40 mm Hg less than baseline) in the presence of evidence of hypoperfusion, despite an intravenous fluid challenge of at least 20 mL/kg.

Criteria for septic shock

•  A need for vasopressor therapy to maintain a mean arterial pressure ≥ 65 mmHg
•  Serum lactate > 2 mM/L which persists after adequate fluid resuscitation

Cryptic septic shock is a new term indicating circulatory dysfunction due to sepsis but without hypotension. Cryptic septic shock is defined as sepsis with severe lactic acidosis (4.0 mM/L or greater) despite a normal or high blood pressure.

Management of sepsis

If the patient has hypoxemia administer adequate oxygen
to maintain arterial hemoglobin oxygen saturation > 95% .
Intravenous saline is administered to all patients with sepsis.
For patients with hypotension, this should be a bolus of 500 mL of saline over 15 minutes. Further fluid administration should be titrated according to the response. To maintain fluid balance urine output and all fluids administered should be recorded. Early goal-directed therapy:
Usually, 500 ml boluses of 0.9% saline up to 1-2 L are empirically administered. Persistent hypotension despite adequate intravenous fluid administration usually requires admission to an ICU and the use of vasopressors. In this case, norepinephrine (noradrenaline) is the preferred drug.
It is helpful to place a central venous line, in order to measure the central venous pressure (CVP). The CVP can be used as a guide for fluid administration. Boluses of 500 ml saline should be administered until CVP >8 cm H₂O .
If the mean arterial pressure <65 mm Hg and CVP >8, then initiate
the intravenous administration of vasopressors, such as norepinephrine (2-8 μg/min) or dopamine (the pressor dose of dopamine is 5-10 μg/kg/min)  to raise blood pressure. ( μg= microgram)
Generally, norepinephrine is preferred, especially if tachycardia or arrhythmias are present.

Prompt and appropriate antimicrobial therapy must be administered as quickly as possible with wide-spectrum intravenous antimicrobials that target the likely causative microorganisms. Such drugs should be given quickly, ideally within 1 hour of admission. Prior to the administration of antibiotics, blood cultures should be taken.
In a patient with sepsis with normal immune function without an identifiable source of infection the initial empirical antibiotic treatment consists of :
Second or third-generation cephalosporin plus gentamicin, or
vancomycin plus third or fourth generation cephalosporin, or
Nafcillin and gentamicin, or
If the patient resides in a nursing facility, or there is a history of recent hospitalizations or a history of methicillin-resistant Staphylococcus aureus then vancomycin should be added to the above antibiotic treatment.
Sepsis in an immunocompromised patient without an identifiable source of infection is treated with:
Piperacillin and gentamicin
Ceftazidime and either nafcillin or vancomycin and gentamicin.
Empiric antibiotic therapy in pediatric patients with sepsis:
Neonates: Ampicillin plus cefotaxime.

Children: Vancomycin plus cefotaxime.

If the source of infection has been identified, or highly suspected, the empirical broad-spectrum antibiotic regimen should be especially effective for  the most likely organisms:
Pulmonary source:
Second or third-generation cephalosporin and gentamicin
Intra-abdominal source:
Ampicillin plus metronidazole plus gentamicin or
Cefoxitin plus gentamicin
Urinary tract source:

Ampicillin or piperacillin plus gentamicin or levofloxacin
Dosage of intravenous (IV) antibiotics:
Ampicillin: 1-2 g (pediatric: 50-200 mg/kg/24 h) IV q 4-6 h
(q 4-6 h= given every 4-6 hours)
Cefoxitin: 1-2 g (pediatric: 100-160 mg/kg/24 h) IV q 6-8 h
Ceftazidime: 1-2 g (pediatric: 100-150 mg/kg/24 h) IV q 8-12 h
Gentamicin: 1-1.5 mg/kg (pediatric: 2-2.5 mg/kg q 8 h) IV q 8h
Metronidazole: Load with 1 g (pediatric: 15 mg/kg) IV, then 500 mg (peds: 7.5 mg/kg) q 6 h
Nafcillin: 1-2 g IV q 4 h (pediatric: 50 mg/kg/24 h divided in  4-6 hour dosing intervals)
Norepinephrine: 2-8 μg/min
Piperacillin: 3- 4 g IV q4–6h
Vancomycin: 500 mg (pediatric: 10 mg/kg) IV q 6 h

It is also very important to identify the likely source of infection from the history, clinical examination and appropriate radiological and laboratory tests. If a specific source of infection is identified its prompt management is vital, for example, debridement of an infected wound, drainage of an infectious pleural effusion (empyema), or surgery to drain an intra-abdominal abscess or to cure another local focus of infection, if present.

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LINK: Emergency medicine book-Table of contents

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Sepsis and septic shock-Clinical advisor -decision support in medicine