ΕΙΣΑΓΩΓΗ ΣΤΙΣ ΛΟΙΜΩΞΕΙΣ

Gram +/- λοιμώξειςSIRS - Σήψη

Ουδετεροπενικός πυρετός

Κωνσταντίνος ΜακαρίτσηςΕπίκουρος Καθηγητής Παθολογίας

Πανεπιστημίου Θεσσαλίας

ΕΙΣΑΓΩΓΗ ΣΤΙΣ ΛΟΙΜΩΞΕΙΣ

Major causes of death

Q: How many people die every year?

In 2012, an estimated 56 million people died worldwide.

Q: What kills more people: infectious diseases or noncommunicable diseases?

Noncommunicable diseases were responsible for 68% of all deaths globally in 2012, up from 60% in 2000. The 4 main NCDs are cardiovascular diseases, cancers, diabetes and chronic lung diseases. Communicable, maternal, neonatal and nutrition conditions collectively were responsible for 23% of global deaths, and injuries caused 9% of all deaths.

Q: What are the main differences between rich and poor countries with respect to causes of death?

In high-income countries, 7 in every 10 deaths are among people aged 70 years and older. People predominantly die of chronic diseases: cardiovascular diseases, cancers, dementia, chronic obstructive lung disease or diabetes. Lower respiratory infections remain the only leading infectious cause of death. Only 1 in every 100 deaths is among children under 15 years.

In low-income countries, nearly 4 in every 10 deaths are among children under 15 years, and only 2 in every 10 deaths are among people aged 70 years and older. People predominantly die of infectious diseases: lower respiratory infections, HIV/AIDS, diarrhoeal diseases, malaria and tuberculosis collectively account for almost one third of all deaths in these countries. Complications of childbirth due to prematurity, and birth asphyxia and birth trauma are among the leading causes of death, claiming the lives of many newborns and infants.

Q: How has the situation changed in the past decade?•Ischaemic heart disease, stroke, lower respiratory infections and chronic obstructive lung disease have remained the top major killers during the past decade.•Noncommunicable diseases (NCDs) were responsible for 68% (38 million) of all deaths globally in 2012, up from 60% (31 million) in 2000. Cardiovascular diseases alone killed 2.6 million more people in 2012 than in the year 2000. •HIV deaths decreased slightly from 1.7 million (3.2%) deaths in 2000 to 1.5 million (2.7%) deaths in 2012. Diarrhoea is no longer among the 5 leading causes of death, but is still among the top 10, killing 1.5 million people in 2012. •Tuberculosis, while no longer among the 10 leading causes of death in 2012, was still among the 15 leading causes, killing over 900 000 people in 2012. •Maternal deaths have dropped from 427 000 in the year 2000 to 289 000 in 2013, but are still unacceptably high: nearly 800 women die due to complications of pregnancy and childbirth every day. •Injuries continue to kill 5 million people each year. Road traffic injuries claimed nearly 3500 lives each day in 2012 – more than 600 more than in the year 2000 – making it among the 10 leading causes in 2012.

Q: How many young children die each year, and why?

•In 2012, 6.6 million children died before reaching their fifth birthday; almost all (99%) of these deaths occurred in low- and middle-income countries.

•The major killers of children aged less than 5 years were prematurity, pneumonia, birth asphyxia and birth trauma, and diarrhoeal diseases. Malaria was still a major killer in sub-Saharan Africa, causing about 15% of under 5 deaths in the region.

•About 44% of deaths in children younger than 5 years in 2012 occurred within 28 days of birth – the neonatal period. The most important cause of death was prematurity, which was responsible for 35% of all deaths during this period.

ΕΙΣΑΓΩΓΗ ΣΤΙΣ ΛΟΙΜΩΞΕΙΣ - ΟΔΟΙ ΜΕΤΑΔΟΣΗΣ

• ΕΝΔΟΓΕΝΗΣ ΛΟΙΜΩΞΗ (Η ενδογενης χλωρίδα του ανθρώπου μπορεί να προκαλέσει λοίμωξη – Ε. coli)

• ΑΕΡΟΓΕΝΗΣ ΔΙΑΣΠΟΡΑ (Μετάδοση μέσω αιωρούμενων σταγονιδίων – Ιοί, Legionella, Ψιττάκωση, Λύσσα)

• ΚΟΠΡΑΝΟΣΤΟΜΑΤΙΚΗ ΔΙΑΣΠΟΡΑ • ΕΝΔΙΑΜΕΣΟΙ ΞΕΝΙΣΤΕΣ ( Ελονοσία, Λεϊσμανίαση)

• ΑΠO ΑΝΘΡΩΠΟ ΣΕ ΑΝΘΡΩΠΟ (Μυκητιάσεις, HIV, HBV)

• AΜΕΣΟΣ ΕΝΟΦΘΑΛΜΙΣΜΟΣ

• ΚΑΤΑΝΑΛΩΣΗ ΜΟΛΥΣΜΕΝΩΝ ΥΛΙΚΩΝ (Βρουκέλλωση, Σαλμονελλώσεις)

ΕΙΣΑΓΩΓΗ ΣΤΙΣ ΛΟΙΜΩΞΕΙΣ - ΠΑΘΟΓΕΝΕΙΑ

• ΕΙΔΙΚΟΤΗΤΑ – Ως προς το είδος του οργανισμού που προσβάλλουν ( π.χ. η αμοιβάδα προσβάλλει μόνο τον άνθρωπο)– Ως προς το όργανο ή τον ιστό που προσβάλλουν ( π.χ. ηπατοτρόποι ιοί A, B, C, E, Strept. Pneumoniae, E. coli)

• ΠΡΟΣΚΟΛΛΗΣΗ ΣΤΟ ΕΠΙΘΗΛΙΟ (Κροσσοί, Προσκολλητίνες [Adhesins], Βιομεμβράνες [Biofilm], Καθετήρες, Προσκόλληση σε ειδικούς υποδοχείς [HIV, Ιστολυτική αμοιβάδα, σκώληκες])

• ΑΠΟΙΚΙΣΜΟΣ-ΔΙΕΙΣΔΥΣΗ • ΔΥΣΛΕΙΤΟΥΡΓΙΑ-ΚΑΤΑΣΤΡΟΦΗ ΙΣΤΩΝ

– Εξωτοξίνες (αναστολή πρωτεϊνοσύνθεσης [διφθερίτιδα], νευροτοξικότητα [Clostr. Tetani, Clostr. Botulinum], εντεροτοξικότητα [E. Coli, Vibrio cholerae])– Eνδοτοξίνη (Η ενδοτοξίνη είναι ο λιποπολυσακχαρίτης του τοιχώματος των Gram αρνητικών μικροβίων και ευθύνεται για την υπόταση, πυρετό, DIC στη σήψη. Ασκεί τη βλαπτική της επίδραση κυρίως μέσω TNF)

THE FEBRILE RESPONSE

ΣΥΝΕΧΗΣ ΠΥΡΕΤΟΣ• Πυρετός > 380C οι διακυμάνσεις του οποίου εντός του

24ώρου δεν υπερβαίνουν τον 10C (τυφοειδής πυρετός, πνευμονία, μελιταίος πυρετός, εξανθηματικός τύφος).

ΥΦΕΣΙΜΟΣ ΠΥΡΕΤΟΣ• Πυρετός > 380C οι διακυμάνσεις του οποίου εντός του

24ώρου υπερβαίνουν τον 10C, χωρίς ποτέ η θερμοκρασία να κατέρχεται σε φυσιολογικά επίπεδα.

• Η υψηλότερη θερμοκρασία εμφανίζεται συνήθως το απόγευμα.

• Αν η υψηλότερη θερμοκρασία εμφανίζεται το πρωί, τότε ονομάζεται ανάστροφος πυρετός.

• Φυματίωση, ιώσεις, βρογχοπνευμονία, διαπυήσεις.

ΤΥΠΟΙ ΠΥΡΕΤΟΥ

ΤΥΠΟΙ ΠΥΡΕΤΟΥ

ΥΦΕΣΙΜΟΣΣΥΝΕΧΗΣ

ΤΥΦΟΕΙΔΗΣ ΠΥΡΕΤΟΣ

ΔΙΑΛΕΙΠΩΝ ΠΥΡΕΤΟΣ• Πυρετός με ταχεία άνοδο > 40-410C οι

διακυμάνσεις του οποίου εντός του 24ώρου υπερβαίνουν τον 10C και κατέρχεται απότομα σε επίπεδα απυρεξίας ή και υποθερμίας.

1. Διαλείπων αμφημερινός ή σηπτικός όταν η άνοδος και η πτώση εμφανίζεται το ίδιο 24ωρο – διπλός, τριπλός αμφημερινός (χολαγγειίτιδα, πυελονεφρίτιδα, σηψαιμία, λεϊσμανίαση).

2. Διαλείπων τριταίος όταν οι παροξυσμοί εμφανίζονται κάθε 48 ώρες (καλοήθης ή κακοήθης τριταίος της ελονοσίας).

3. Διαλείπων τεταρταίος όταν οι πυρετικοί παροξυσμοί εμφανίζονται κάθε 72 ώρες (καλοήθης τεταρταίος της ελονοσίας).

ΤΥΠΟΙ ΠΥΡΕΤΟΥ

ΤΥΠΟΙ ΠΥΡΕΤΟΥ

ΔΙΑΛΕΙΠΩΝ ΑΜΦΗΜΕΡΙΝΟΣ Ή ΣΗΠΤΙΚΟΣ ΠΥΡΕΤΟΣ

Plasmodium vivaxPlasmodium ovale Plasmodium malariae Plasmodium falciparum

ΠΥΡΕΤΟΣ ΣΕ ΧΡΟΝΙΑ ΕΛΟΝΟΣΙΑ

καλοήθης τριταίος

καλοήθης τεταρταίος

κακοήθης τριταίος

ΚΥΜΑΤΟΕΙΔΗΣ ΠΥΡΕΤΟΣ• Πυρετός κατά τον οποίο πυρετικά κύματα

διάρκειας 1-2 εβδομάδων εναλλάσσονται βαθμιαία (όχι απότομα) με μεσοδιαστήματα πυρετίου ή πλήρους απυρεξίας (χρονία βρουκέλλωση, νόσος Hodgkin, σαρκώματα).

ΥΠΟΣΤΡΟΦΟΣ ΠΥΡΕΤΟΣ• Πυρετός κατά τον οποίο πυρετικά κύματα

διάρκειας λίγων ημερών εναλλάσσονται απότομα με ολιγοήμερα μεσοδιαστήματα πλήρους απυρεξίας (Borreliosis, βρογχεκτασίες, εμπύηματα).

ΤΥΠΟΙ ΠΥΡΕΤΟΥ

ΠΥΡΕΤΟΣ ΣΕ ΧΡΟΝΙΑ ΒΡΟΥΚΕΛΛΩΣΗ

ΚΥΜΑΤΟΕΙΔΗΣ ΠΥΡΕΤΟΣ

ΠΥΡΕΤΟΣ Pel-Ebstein

N. Hogkin με διήθηση παραορτικών λεμφαδένων

ΥΠΟΣΤΡΟΦΟΣ ΠΥΡΕΤΟΣ

Borreliosis

ΔΕΚΑΤΙΚΟ ΠΥΡΕΤΙΟ Ή ΔΕΚΑΤΙΚΗ ΠΥΡΕΤΙΚΗ ΚΙΝΗΣΗΗ θερμοκρασία κυμαίνεται από 37,20C- 37,80C, συνοδεύεται από αίσθημα αδυναμίας και ήπιες εφιδρώσεις και εμφανίζεται κυρίως κατά τις απογευματινές ώρες. Σπάνια αποδίδεται σε οργανικά αίτια και μπορεί να οφείλεται σε κακή θερμομέτρηση.

Πυρετός αδιευκρίνιστης αιτιολογίας ορίζεται 1. πυρετός > 38,30C κατ΄ εξακολούθηση2. διάρκεια > 3 εβδομάδες3. αδυναμία ανεύρεσης αιτίου παρά την διεξοδική διερεύνηση επί 1 εβδομάδα στο νοσοκομείο (Κλασικός ορισμός Petersdorf το 1961)

Σύγχρονη Ταξινόμηση• Κλασικός πυρετός αδιευκρίνιστης αιτιολογίας • Νοσοκομειακός πυρετός• Πυρετός σε ανοσοκατασταλμένους

(ουδετεροπενικός πυρετός)• Πυρετός σχετιζόμενος με λοίμωξη από HIV

ΠΥΡΕΤΟΣ ΑΔΙΕΥΚΡΙΝΙΣΤΗΣ ΑΙΤΙΟΛΟΓΙΑΣ (FUO)

ΑΙΤΙΑ ΠΥΡΕΤΟΥ ΑΔΙΕΥΚΡΙΝΙΣΤΗΣ ΑΙΤΙΟΛΟΓΙΑΣ

ΑΙΤΙΑ ΠΥΡΕΤΟΥ ΑΔΙΕΥΚΡΙΝΙΣΤΗΣ ΑΙΤΙΟΛΟΓΙΑΣ

ΑΙΤΙΑ ΠΥΡΕΤΟΥ ΑΔΙΕΥΚΡΙΝΙΣΤΗΣ ΑΙΤΙΟΛΟΓΙΑΣ

ΑΙΤΙΑ ΠΥΡΕΤΟΥ ΜΕΤΑ ΑΠΟ ΤΑΞΙΔΙ• Η ελονοσία αποτελεί το συχνότερο ειδικό αίτιο

πυρετού και το συχνότερο αίτιο εισαγωγής στο νοσοκομείο.

• Ο δάγγειος πυρετός αποτελεί το δεύτερο συχνότερο αίτιο.

• Λοιμώδης Μονοπυρήνωση (EBV-CMV) • Σαλμονελλώσεις (S. typhi, paratyphi)• Ρικετσιώσεις• Κοινές λοιμώξεις 30% (αναπνευστικού, ΓΕΣ και

ουροποιητικού).• Μη λοιμώδη αίτια 3%• Μη ταυτοποίηση του αιτίου σε 22% των

περιπτώσεων.

Freedman D et al. N Engl J Med, Jan 2006

Δάγγειος: 8%

Ελονοσία: 4%

Ελονοσία: 35%

Ρικετσιώσεις: 4%

Δάγγειος: 12%

Ελονοσία: 9%

Etiology and Outcome of Fever After a Stay in the Tropics. E. Bottieau, et al. Arch Intern Med. 2006;166:1642-1648.

N=1743

ΠΥΡΕΤΟΣ ΚΑΙ ΓΕΩΓΡΑΦΙΚΟΣ ΠΡΟΟΡΙΣΜΟΣ

ΣΗΨΗ – ΣΗΠΤΙΚΗ ΚΑΤΑΠΛΗΞΙΑ

ΣΗΨΗ – ΣΗΠΤΙΚΗ ΚΑΤΑΠΛΗΞΙΑ

ΣΗΨΗ – ΣΗΠΤΙΚΗ ΚΑΤΑΠΛΗΞΙΑ

ΣΗΨΗ – ΣΗΠΤΙΚΗ ΚΑΤΑΠΛΗΞΙΑ

Sepsis is defined as suspected or proven infection plus a

systemic inflammatory response syndrome [SIRS] (e.g.,

fever, tachycardia, tachypnea, and leukocytosis).

Severe sepsis is defined as sepsis with organ

dysfunction (hypotension, hypoxemia, oliguria, metabolic

acidosis, thrombocytopenia).

Septic shock is defined as severe sepsis with

hypotension, despite adequate fluid resuscitation.

Septic shock and multiorgan dysfunction are the most common

causes of death in patients with sepsis.

The mortality rates associated with severe sepsis and septic

shock are 25 to 30% and 40 to 70%, respectively.

There are approximately 750,000 cases of sepsis a year in the United

States, and the frequency is increasing, given an aging population with

increasing numbers of patients infected with treatment-resistant organisms,

patients with compromised immune systems, and patients who undergo

prolonged, high-risk surgery.

ΣΗΨΗ – ΣΗΠΤΙΚΗ ΚΑΤΑΠΛΗΞΙΑ

First, rapid diagnosis (within the first 6 hours) and expeditious

treatment are critical, since early, goal-directed therapy can be very

effective.

Second, multiple approaches are necessary in the treatment of sepsis.

Third, it is important to select patients for each given therapy with great

care, because the efficacy of treatment — as well as the likelihood and

type of adverse results — will vary, depending on the patient.

The rationale for the use of therapeutic targets in sepsis has arisen

from concepts of pathogenesis (Table 1).

ΣΗΨΗ – ΣΗΠΤΙΚΗ ΚΑΤΑΠΛΗΞΙΑ

Microorganisms stimulate specific humoral and cell-mediated adaptive immune responses that amplify innate immunity.

B cells release immunoglobulins that bind to microorganisms, facilitating their delivery by antigen-presenting cells to natural killer cells and neutrophils that can kill the microorganisms.

T-cell subgroups are modified in sepsis. Helper (CD4+) T cells can be categorized as type 1 helper (Th1) or type 2 helper (Th2) cells.

Th1 cells generally secrete proinflammatory cytokines such as TNF-α  and interleukin-1β.

Th2 cells secrete antiinflammatory cytokines such as interleukin-4 and interleukin-10, depending on the infecting organism, the burden of infection, and other factors.

ΣΗΨΗ – ΣΗΠΤΙΚΗ ΚΑΤΑΠΛΗΞΙΑ

Host defenses can be categorized according to innate and adaptive immune

system responses.

The innate immune system responds rapidly by means of pattern-recognition

receptors (e.g., toll-like receptors [TLRs]) that interact with highly conserved

molecules present in microorganisms.

For example, TLR-2 recognizes a peptidoglycan of gram-positive bacteria, whereas

TLR-4 recognizes a lipopolysaccharide of gram-negative bacteria.

Binding of TLRs to epitopes on microorganisms stimulates intracellular signaling,

increasing transcription of proinflammatory molecules such as tumor necrosis

factor (TNF-α ) and interleukin-1β , as well as antiinflammatory cytokines such as

interleukin-10.

Proinflammatory cytokines up-regulate adhesion molecules in neutrophils and

endothelial cells.

Although activated neutrophils kill microorganisms, they also injure endothelium

by releasing mediators that increase vascular permeability, leading to the flow of

protein-rich edema fluid into lung and other tissues.

In addition, activated endothelial cells release nitric oxide, a potent vasodilator that

acts as a key mediator of septic shock.

ΣΗΨΗ – ΣΗΠΤΙΚΗ ΚΑΤΑΠΛΗΞΙΑ

An important aspect of sepsis is the alteration of the procoagulant–

anticoagulant balance, with an increase in procoagulant factors and a

decrease in anticoagulant factors. Lipopolysaccharide stimulates

endothelial cells to up-regulate tissue factor, activating coagulation.

Fibrinogen is then converted to fibrin, leading to the formation of

microvascular thrombi and further amplifying injury.

Key to an understanding of sepsis is the recognition that the

proinflammatory and procoagulant responses can be amplified by

secondary ischemia (shock) and hypoxia (lung injury) through the

release of tissue factor and plasminogen-activator inhibitor 1.

ΣΗΨΗ – ΣΗΠΤΙΚΗ ΚΑΤΑΠΛΗΞΙΑ

Procoagulant Response in Sepsis

Normally, natural anticoagulants (protein C and protein S), antithrombin III, and tissue factor–pathway inhibitor (TFPI) dampen coagulation, enhance fibrinolysis, and remove microthrombi. Thrombin-α  binds to thrombomodulin on endothelial cells, which dramatically increases activation of protein C to activated protein C. Protein C forms a complex with its cofactor protein S.

Activated protein C proteolytically inactivates factors Va and VIIIa and decreases the synthesis of plasminogen-activator inhibitor 1 (PAI-1).

ΣΗΨΗ – ΣΗΠΤΙΚΗ ΚΑΤΑΠΛΗΞΙΑ

In contrast, sepsis increases the synthesis of PAI-1. Sepsis also decreases the levels of protein C, protein S, antithrombin III, and TFPI. Lipopolysaccharide and tumor necrosis factor (TNF-α) decrease the synthesis of thrombomodulin and endothelial protein C receptor (EPCR), thus decreasing the activation of protein C. Sepsis further disrupts the protein C pathway because sepsis also decreases the expression of EPCR, which amplifies the deleterious effects of the sepsis-induced decrease in levels of protein C. Lipopolysaccharide and TNF-α also increase PAI-1 levels so that fibrinolysis is inhibited. The clinical consequences of the changes in coagulation caused by sepsis are increased levels of markers of disseminated intravascular coagulation and widespread organ dysfunction.

ΣΗΨΗ – ΣΗΠΤΙΚΗ ΚΑΤΑΠΛΗΞΙΑ

Host immunosuppression has long been considered a factor in late death in patients with sepsis, since the sequelae of anergy, lymphopenia, hypothermia, and nosocomial infection all appear to be involved.

When stimulated with lipopolysaccharide ex vivo, monocytes from patients with sepsis express lower amounts of proinflammatory cytokines than do monocytes from healthy subjects, possibly indicating relative immunosuppression.

ΣΗΨΗ – ΣΗΠΤΙΚΗ ΚΑΤΑΠΛΗΞΙΑ

Multiorgan dysfunction in sepsis may be caused, in part, by a shift to an antiinflammatory phenotype and by apoptosis of

key immune, epithelial, and endothelial cells. In sepsis, activated helper T cells evolve from a Th1 phenotype, producing proinflammatory cytokines, to a Th2 phenotype, producing antiinflammatory cytokines.

In addition, apoptosis of circulating and tissue lymphocytes (B cells and CD4+ T cells) contributes to immunosuppression.

Apoptosis is initiated by proinflammatory cytokines, activated B and T cells, and circulating glucocorticoid levels, all of which are increased in sepsis.

Increased levels of TNF-α and lipopolysaccharide during sepsis may also induce apoptosis of lung and intestinal epithelial cells.

ΣΗΨΗ – ΣΗΠΤΙΚΗ ΚΑΤΑΠΛΗΞΙΑ

• The altered signaling pathways in sepsis ultimately lead to

tissue injury and multiorgan dysfunction.

• Cardiovascular dysfunction is characterized by circulatory

shock and the redistribution of blood flow, with decreased

vascular resistance, hypovolemia, and decreased myocardial

contractility associated with increased levels of nitric oxide,

TNF-α, interleukin-6, and other mediators.

• Respiratory dysfunction is characterized by increased

microvascular permeability, leading to acute lung injury.

• Renal dysfunction in sepsis, may be profound, contributing

to morbidity and mortality.

ΣΗΨΗ – ΣΗΠΤΙΚΗ ΚΑΤΑΠΛΗΞΙΑ

The cornerstone of emergency management of sepsis is early, goal-directed therapy, plus lung-protective ventilation, broad-spectrum antibiotics, and possibly activated protein C.

In a randomized, controlled trial in which patients with severe sepsis and septic shock received early, goal-directed, protocol-guided therapy during the first 6 hours after enrollment or the usual therapy.

Central venous oxygen saturation was monitored continuously with the use of a central venous catheter. Crystalloids were administered to maintain central venous pressure at 8 to 12 mm Hg. Vasopressors were added if the mean arterial pressure was less than 65 mm Hg; if central venous oxygen saturation was less than 70%, erythrocytes were transfused to maintain a hematocrit of more than 30%. Norepinephrine was added if the central venous pressure, mean arterial pressure, and hematocrit were optimized yet venous oxygen saturation remained below 70%. Early, goal-directed therapy in that study decreased mortality at 28 and 60 days as well as the duration of hospitalization.

The mechanisms of the benefit of early, goal-directed therapy are unknown but may include reversal of tissue hypoxia and a decrease in inflammation and coagulation defects.

Early, Goal-Directed Therapy

Rivers E et al. N Engl J Med 2001;345:1368-1377

Early, Goal-Directed Therapy

Therapeutic Plan Based on the Early and Later Stages of Sepsis

ΟΥΔΕΤΕΡΟΠΕΝΙΚΟΣ ΠΥΡΕΤΟΣ

ΕΠΙΠΛΟΚΕΣ ΧΗΜΕΙΟΘΕΡΑΠΕΙΑΣ

1. Εξαγγείωση ΧΜΘ παράγοντα

(Ιστική νέκρωση)

2. Καταστολή μυελού - Λοιμώξεις

3. Γαστρεντερικό

(Στοματίτιδα-Διάρροια-Ναυτία-Έμετος)

4. Διάμεση πνευμονίτιδα

5. Αιμορραγική Κυστίτιδα (Κυκλοφωσφαμίδη)

6. Σύνδρομο λύσης όγκου

( Κ, PO4, Ουρικό, ΟΝΑ)

Clinical Infectious Diseases 2011;52(4):e56–e93

• Fever in neutropenic patients is classically defined as a single oral temperature of >38.3∘C (101∘F), or a temperature of >38.0∘C (100.4∘F) sustained over a 1-h period.

• Although, it is known that a neutropenic patient can be infected without fever or stay subfebrile, the definition of neutropenia is an absolute neutrophil count (ANC) < 1500 cells/μL,

• severe neutropenia is defined as an ANC < 500 cells/μL or that is expected to decrease below 500 cells/μL during the next 48 hours,

• and profound neutropenia is an ANC < 100 cells/μL.

• The risk of clinically important infection rises as the neutrophil count falls below 500 cells/ μL and is higher in those with a prolonged duration of neutropenia (>7 days).

Adv Hematol. 2014;2014:986938

Fever occurs frequently during chemotherapy-induced neutropenia: 10%–50% of patients with solid tumors and >80% of those with hematologic malignancies will develop fever during ≥1 chemotherapy cycle associated with neutropenia.

Most patients will have no infectious etiology documented.

Clinically documented infections occur in 20%–30% of febrile episodes; common sites of tissue-based infection include the intestinal tract, lung, and skin.

Bacteremia occurs in 10%–25% of all patients, with most episodes occurring in the setting of prolonged or profound neutropenia (ANC<100 neutrophils/mm3)

Clinical Infectious Diseases 2011;52(4):e56–e93

Risk Assessment

1. Assessment of risk for complications of severe infection should be undertaken at presentation of fever (A-II). Risk assessment may determine the type of empirical antibiotic therapy (oral vs intravenous [IV]), venue of treatment (inpatient vs outpatient), and duration of antibiotic therapy (A-II).

2. Most experts consider high-risk patients to be those with anticipated prolonged (>7 days duration) and profound neutropenia (absolute neutrophil count [ANC] <100 cells/μL following cytotoxic chemotherapy) and/or significant medical co-morbid conditions, including hypotension, pneumonia, new-onset abdominal pain, or neurologic changes. Such patients should be initially admitted to the hospital for empirical therapy (A-II).

Clinical Infectious Diseases 2011;52(4):e56–e93

Risk Assessment

3. Low-risk patients, including those with anticipated brief (<7 days duration) neutropenia or no or few comorbidities, are candidates for oral empirical therapy (A-II).

4. Formal risk classification may be performed using the Multinational Association for Supportive Care in Cancer (MASCC) scoring system (B-I).

i. High-risk patients have a MASCC score ,21 (B-I). Allpatients at high risk by MASCC or by clinical criteria should be initially admitted to the hospital for empirical antibiotic therapy if they are not already inpatients (B-I).ii. Low-risk patients have a MASCC score>21 (B-I). Carefully selected low-risk patients may be candidates for oral and/or outpatient empirical antibiotic therapy (B-I).

Clinical Infectious Diseases 2011;52(4):e56–e93

Adv Hematol. 2014;2014:986938

N Engl J Med. 2013 Mar 21;368(12):1131-9.

N Engl J Med. 2013 Mar 21;368(12):1131-9.

II. What Specific Tests and Cultures Should be Performed during the Initial Assessment?

Recommendations5. Laboratory tests should include a complete blood cell (CBC) count with differential leukocyte count and platelet count; measurement of serum levels of creatinine and blood urea nitrogen; and measurement of electrolytes, hepatic transaminase enzymes, and total bilirubin (A-III).

6. At least 2 sets of blood cultures are recommended, with a set collected simultaneously from each lumen of an existing central venous catheter (CVC), if present, and from a peripheral vein site; 2 blood culture sets from separate venipunctures should be sent if no central catheter is present (A-III). Blood culture volumes should be limited to,1% of total blood volume (usually 70 mL/kg) in patients weighing, 40 kg (C-III).

7. Culture specimens from other sites of suspected infection should be obtained as clinically indicated (A-III).

8. A chest radiograph is indicated for patients with respiratory signs or symptoms (A-III).

Clinical Infectious Diseases 2011;52(4):e56–e93

III. In Febrile Patients With Neutropenia, What Empiric Antibiotic Therapy Is Appropriate and in What Venue?

RecommendationsGeneral Considerations9. High-risk patients require hospitalization for IV empirical antibiotic therapy; monotherapy with an antipseudomonal b-lactam agent, such as cefepime, a carbapenem (meropenem or imipenem-cilastatin), orpiperacillin-tazobactam, is recommended (A-I). Other antimicrobials (aminoglycosides, fluoroquinolones, and/or vancomycin) may be added to the initial regimen for management of complications (eg, hypotension and pneumonia) or if antimicrobial resistance is suspected or proven (B-III).

10. Vancomycin (or other agents active against aerobic gram positive cocci) is not recommended as a standard part of the initial antibiotic regimen for fever and neutropenia (A-I). These agents should be considered for specific clinical indications, including suspected catheter-related infection, skin or soft-tissue infection, pneumonia, or hemodynamic instability.

Clinical Infectious Diseases 2011;52(4):e56–e93

III. In Febrile Patients With Neutropenia, What Empiric Antibiotic Therapy Is Appropriate and in What Venue?

11. Modifications to initial empirical therapy may be considered for patients at risk for infection with the following antibiotic-resistant organisms, particularly if the patient’s condition is unstable or if the patient has positive blood culture results suspicious for resistant bacteria (B-III). These include methicillin-resistant Staphylococcus aureus (MRSA), vancomycin-resistant enterococcus (VRE), extended-spectrum b-lactamase (ESBL)–producing gram-negative bacteria, and carbapenemase-producing organisms, including Klebsiella pneumoniae carbapenemase (KPC). Risk factors include previous infection or colonization with the organism and treatment in a hospital with high rates of endemicity.

i. MRSA: Consider early addition of vancomycin, linezolid, or daptomycin (B-III).ii. VRE: Consider early addition of linezolid or daptomycin (B-III).iii. ESBLs: Consider early use of a carbapenem (B-III).iv. KPCs: Consider early use of polymyxin-colistin or tigecycline (C-III).

Clinical Infectious Diseases 2011;52(4):e56–e93

III. In Febrile Patients With Neutropenia, What Empiric Antibiotic Therapy Is Appropriate and in What Venue?12. Most penicillin-allergic patients tolerate cephalosporins, but those with a history of an immediate-type hypersensitivity reaction (eg, hives and bronchospasm) should be treated with a combination that avoids b-lactams and carbapenems, such as ciprofloxacin plus clindamycin or aztreonam plus vancomycin (A-II).13. Afebrile neutropenic patients who have new signs or symptoms suggestive of infection should be evaluated and treated as high-risk patients (B-III).14. Low-risk patients should receive initial oral or IV empirical antibiotic doses in a clinic or hospital setting; They may be transitioned to outpatient oral or IV treatment if they meet specific clinical criteria (A-I).i. Ciprofloxacin plus amoxicillin-clavulanate in combination is recommended for oral empirical treatment (A-I). Other oral regimens, including levofloxacin or ciprofloxacin monotherapy or ciprofloxacin plus clindamycin, are less well studied but are commonly used (B-III).ii. Patients receiving fluoroquinolone prophylaxis should not receive oral empirical therapy with a fluoroquinolone (A-III).iii. Hospital re-admission or continued stay in the hospital is required for persistent fever or signs and symptoms of worsening infection (A-III).

Adv Hematol. 2014;2014:986938

V. How Long Should Empirical Antibiotic Therapy be Given?

Recommendations

22. In patients with clinically or microbiologically documented infections, the duration of therapy is dictated by the particular organism and site; appropriate antibiotics should continue for at least the duration of neutropenia (until ANC is > 500 cells/mm3) or longer if clinically necessary (B-III).

23. In patients with unexplained fever, it is recommended that the initial regimen be continued until there are clear signs of marrow recovery; the traditional endpoint is an increasing ANC that exceeds 500 cells/mm3 (B-II).

24. Alternatively, if an appropriate treatment course has been completed and all signs and symptoms of a documented infection have resolved, patients who remain neutropenic may resume oral fluoroquinolone prophylaxis until marrow recovery (C-III).

N Engl J Med. 2013 Mar 21;368(12):1131-9.

X. What Is the Role of Hematopoietic Growth Factors (G-CSF or GM-CSF) in Managing Fever and Neutropenia?

Recommendations

41. Prophylactic use of myeloid colony-stimulating factors (CSFs; also referred to as hematopoietic growth factors) should be considered for patients in whom the anticipated risk of fever and neutropenia is >20% (A-II).

42. CSFs are not generally recommended for treatment of established fever and neutropenia (B-II).

XII. What Environmental Precautions Should be Taken When Managing Febrile Neutropenic Patients?

Recommendations48. Hand hygiene is the most effective means of preventingtransmission of infection in the hospital (A-II).49. Standard barrier precautions should be followed for all patients, and infection-specific isolation should be used for patients with certain signs or symptoms (A-III).50. HSCT recipients should be placed in private (ie, single patient) rooms (B-III). Allogeneic HSCT recipients should be placed in rooms with >12 air exchanges/h and high-efficiency particulate air (HEPA) filtration (A-III).51. Plants and dried or fresh flowers should not be allowed in the rooms of hospitalized neutropenic patients (B-III).52. Hospital work exclusion policies should be designed to encourage health care workers (HCWs) to report their illnesses or exposures (A-II).

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