Fever, Sepsis, and Vector Borne Illness

What is the definition of a fever?

regulated rise in body temperature to a new "set point" above the normal range

What induces fevers?

pyrogens

What is the average oral temp, and what is considered a fever?

oral temp: 98.0 F (95.5 - 99.9 F)

fever: 100.4 F

Name the temperatures of rectal, tympanic, axillary, and forehead temperatures, and which are the most reliable, and the best replacements

rectal: one degree above oral (99.6 F)

tympanic: one degree above oral (99.6 F)

axillary: one degree below oral (97.6 F)

forehead: one degree below oral (97.6 F)

rectal is most reliable, oral and tympanic are good relplacemnents

What is the criteria for a fever of unknown origin (FUO) diagnosis?

- temperature is at least 100.9 F (38.3 C)

- several fevers throughout 3 week duration

- diagnosis of cause has not been made after

- 3 outpatient visits with 1 week of intensive outpatient w/u OR 3 days of hospitalization with inpatient w/u

What is the criteria for healthcare/hospital-associated FUO?

- temp at least 100.9 F serially despite 3+ days of unrevealing inpatient w/u

- fever-producing illness not present at admission

What infections do we worry about most commonly with broad causes of FUO?

- TB and endocarditis are the MC of systemic infection with FUO

- Abscesses are the MC of localized infection with FUO

What are the most common neoplasms associated with broad FUO causes?

lymphoma and leukemia

What other neoplasms can be associated with broad FUO causes?

liver tumors and RCC commonly associated with fever

What does a fever diary consist of?

date, time, temp, duration, rout of measurements, sxs's, antipyretics

Why avoid antipyretics?

avoid when possible for accuracy of the diary (NSAIDs or acetaminophen PRN)

FUO management

- fever diary

- discontinue nonesssential, potentially fever-producing drugs

- empiric antibiotics or antifungals if infectious diagnosis suspected

- glucocorticoid if suspected CGA/PMR

What is sepsis?

life-threatening organ dysfunction caused by a dysregulated response to infection

What is septic shock?

SEPSIS + the patient requires vasopressors to maintain mean arterial pressure (MAP) >65 mmHg and has a lactate >2 mmol/L despite adequate fluid resuscitation

What are the indications for systemic inflammatory response syndrome (SIRS)?

- fever (>100.4 F) or hypothermia (<96.8 F)

- HR >90 bpm

- RR >20 bpm or arterial carbon dioxide tension (PaCO2) <32 mmHg

- abnormal WBC count (>12,000/uL or <4000/uL or >10% immature (band) forms - "left shift")

Why does a respiratory rate >20 bpm occur in SIRS?

the body is trying to compensate for metabolic acidosis, which happens a lot in infections

What is the underlying theme of sepsis?

inflammatory response exceeds the cofines of the local infection and becomes systemic

True or False: Many signs and symptoms of sepsis and septic shock are specific to the underlying cause

True

What are the other findings (signs and symptoms) of sepsis and septic shock that occur, and which one should activate the alarm bells that we're definitely looking at sepsis?

- altered mental status (confusion, lethargy, obtundation)

- SOB/tachypnea/hypoxia

- Hypotension, tachycardia

- fever/chills/malaise

- warm/flushed skin early -> cool skin late

In sepsis and/or septic shock, imaging is directed at determining an infectious source. What are the 3 types we use most often, and when are they indicated?

1. CXR - pulmonary source

2. CT - intra-abdominal abscess, perforation, pyelonephritis

- also considered if CXR is unrevealing but pulmonary source is still predicted

3. Echocardiogram (TTE first, then TEE if TTE negative) - infective endocarditis, unexplained or persistent bacteremia

What would we see on an echo in a patietn with infective endocarditis?

vegetations visualized on echo

What are the treatments for sepsis and septic shock?

1. antibiotics

2. intravenous (IV) fluid resuscitation

3. vasopressors

What do we start with when giving sepsis/septic shock antibiotic treatment?

start with broad spectrum antibiotics (vancomycin + piperacillin/tazobactam or vancomycin + cefepime)

When do we change the broad spectrum antibiotic treatment in sepsis/septic shock?

once the source/pathogen has been identified we can narrow the antibiotic spectrum accordingly

What are some of the issues people struggle with after having sepsis and/or septic shock?

weakness, reduced function, cognitive decline, depression, and reduced quality of life

What is the post-discharge prognosis of sepsis and/or septic shock?

- 50% are re-hospitalized within one year

- increased risk for death for 2 years (most within 6 months)

What causes Lyme disease infection?

borellia burgdorferi

When does Lyme disease stage 3 (late disease) take place?

months to years later

What will be the main complaints from patients in lyme disease stage 3 (late disease)?

joint pain

how is lyme (early) disease (erythema migrans) diagnosed?

clincal dx, no serology needed

How do you diagnose Lyme (disseminated/late) disease?

two-tiered serologic testing

1. ELISA (preferred) or immunofluorescence assay for B. burgdoferi Abs (if negative no further testing)

2. Western blot

- positive = IgM against 2 specific antigens ("bands") OR IgG against 5 antigens ("bands")

What is a modified two-tiered testing for lyme (disseminated/late) disease?

ELISA one time and if positive ELISA again

What is the treatment for Lyme (late persistent) disease?

for the arthritis doxy or amoxicillin PO x 28 days (cefuroxime if others CI); if this doesn't help despite PO tx, move to ceftriaxone IV x 14-28 days

What is the lyme disease prognosis?

symptoms usually resolve within 4 weeks after treatment

How is the postinfectious lyme arthritis prognosis?

- persistent inflammatory arthritis despite course of PO and IV abx

- manage in conjunction with rheumatology (DMARDs - usually short term)

- may last months to years; resolves spontaneously

What is the prognosis of post-treatment lyme disease syndrome?

- persistent symptoms after lyme treatment, occuring within 6 months of treatment and persisting at least 6 months

- fatigue, cognitive issues, diffuse MSK pain

- prolonged abx is not recommended

True or false: Lyme disease reinfection is very common

False; uncommon, but possible

What are the prevention options for RMSF

- protective clotting

- insect repellent

- tick checks and bathing

- removal of tick

What is the incubation period of West Nile virus, and how does it usually present?

incubation: 2-14 days

presentation: most people are asymptomatic (about 20-40%)

What are the 3 presentations of West Nile virus neuroinvasive disease?

1. meningitis

2. encephalitis

3. flaccid paralysis

What are the signs and symptoms of meningitis presentation of West Nile virus neuroinvasive disease?

headache, photophobia, meningeal signs

What are the signs and symptoms of encephalitis presentation of West Nile virus neuroinvasive disease?

- ranges from mild confusion to severe encephalopathy/coma/death

- tremor, myoclonus, rigidity, postural instability, bradykinesia

What are the signs and symptoms of flaccid paralysis presentation of West Nile virus neuroinvasive disease?

- asymmetric, rapidly developing limb weakness

- 1/3 recover to baseline, 1/3 partially improve, 1/3 do not improve

What is the most common clinical presentation of malaria?

paroxysms of chills, fever, then diaphoresis, ocurring every 48-72 hours

What are other signs and symptoms that are possible in malaria?

malaise, HA, myalgia/arthralgia, cough, chest pain, pulmonary edema, N/V/D/abdominal pain, anorexia, jaundice, hepatomegaly, splenomegaly

What is severe disease characterized by in malaria?

altered mental status/seizures, severe anemia, couagulopathy, hypoglycemia, metabaolic acidosis, respiratory, liver, and renal failure, circulatory collapse/shock

What's the clincal presentation of cerebral malaria?

AMS, violent behavior, seizure, coma, death, very high fever, accounts for 80% of malaria deaths

What causes cerebral malaria?

cerebral edema secondary to cerebral sequestration of RBCs

What is the general pathophysiology of fevers

a set point increase leads to vasoconstriction (reduces heat loss) -> thermogenesis in fat and muscle by uncoupling proteins (increases heat production) -> behavioral changes (warm room, blankets, clothes) -> shivering (rapidly raises temp) -> leading to head production exceeding heat loss

What is Step 1 of fever pathophysiology?

presence/detection of an exogenous pyrogen from bacteria, virus or fungi

What is Step 2 of fever pathophysiology?

macrophages and monocytes and other immune cells release cytokines that are endogenous pyrogens

What is Step 3 of fever pathophysiology?

endogenous pyrogens are sent to the hypothalamic thermoregulatory center where they induce synthesis of prostaglandins

What is Step 4 of fever pathophysiology?

prostaglandin synthesis signals the hypothalamic thermoregulatory center to increase the new "set point"

What is Step 5 of fever pathophysiology?

to reach the new "set point," the hypothalamus induces physiologic changes which include vasoconstriction and thermogenesis

- heat generated > heat loss = fever

- vasodilation - sweating when the fever breaks

What is neutropenic FUO?

temp at least 100.9 F or at least 100.4 F sustained x 1hr serially over at least 3 days with neutrophils <500 cells/microliter

What is HIV-associated FUO?

temperature of at least 100.9 F serially for at least 3 weeks outpatient or at least 3 days inpatient despite unrevealing w/u; CD4 count <200 cells/microliter

What do most FUO cases represent?

unusual manifestations of common disease

What is the breakdown of FUO causes in adults?

infection: 25-40%

cancer: 25-40%

autoimmune: 10-20%

What is the breakdown of FUO causes in kids?

infection: 50%

cancer: 5-10%

autoimmune: 10-20%

What % of FUO cases have an undetermined cause, and of those what % resolve?

50% are undetermined; 75% of these cases will resolve fever spotaneously, the remainder develop more clear disease symptoms

What are some autoimmune causes of FUO?

giant cell arteritis, polymyalgia, rheumatica, rheumatoid arthritis, lupus, polyarteritis nodosa

What are the misc. causes of FUO?

thyroiditis, sarcoidosis, Whipple dz, familial mediterranean fever, pulmonary embolism, alcoholic hepatitis, drug-induced fever

What constitutional symptoms do we ask about for FUO diagnosis?

chills, night sweats, weight loss, LAD

What parts of a PMHx are we looking for when diagnosing FUO?

CA, TB, IBD, SLE, RA, other autoimmune disease, dental hx

What parts of a FHx are we looking for when diagnosing FUO?

CA, autoimmune disease

What are important factors to consider with FUO diagnosis?

- hx of immunocompromise

- valvular or congenital heart disease or hx of murmur

- implanted devices (pacemaker, prosthetic joints)

- travel

What labs/imaging/cultures or tissue must we do for diagnostic workup of FUO?

labs: CBC and CMP

imaging: CXR

cultures/tissue: blood culture, UA and urine culture

What do we do for FUO management if a cause isn't found?

1. continue monitoring

2. whole body scan

How can we do a whole body scan for FUO management if the cause is unknown?

- fluorodeoxyglucose (FDG) PET/CT (preferred)

- labeled WBC scan (alternative)

True or False: 1.5 million cases of sepsis per year in US, with 10% being hospitalized adults

false; 1.7 million cases/year, with 6% being hospitalized adults

__________ sepsis deaths and discharge to hospice annually in USA

350,000

sepsis causes _____ total global deaths

1/5

True or False: 40% overall mortality for USA hospitalized septic patients, and up to 15% mortality for septic shock

false; 15% overall mortality for hospitilized septic patients, and up to 40% mortality for septic shock

What are the RFs for increased sepsis mortality?

diabetes, obesity, chronic renal and hepatic insufficiency, chronic neurological disease, chronic heart or lung disease, cancer, immunocompromised

What is sepsis usually due to?

bacteria; 50/50 gram positive/gram negative

What are the most prevelant gram positive causes of sepsis?

S. aureus, strep species, enterococcus species

What are the most prevalent Gram-negative causes of sepsis?

E. coli, klebsiella species, and pseudomonas aeruginosa

Why are fungal causes of sepsis (like candida) rising?

due to increased immunosuppression and neutropenia

What are the most common sites of sepsis?

urinary, respiratory, abdominal, skin/soft tissue, devices

What is step 1 of sepsis pathophysiology?

localized infection leads to spread infection into blood or release of bacterial toxins into blood -> widespread inflammatory response

What is step 2 of sepsis pathophysiology?

toxins activate immune cells

What is step 3 of sepsis pathophysiology?

immune cells release proinflammatory cytokines (IL-1, IL-12, IL-18, tumor necrosis factor (TNF) alpha, interferon)

What is step 4 of sepsis pathophysiology?

inflammatory cytokines will activate complement pathway, alter endothelium and coagulation function, and downregulate the adaptive (specific) immune system

What is step 5 of sepsis pathophysiology?

- vascular endothelium is activated by pathogen and host products

- increased tissue factor expression by endothelium (initiates coagulation cascade and promotes leukocyte adhesion to endothelium)

- increased vascular permeability (third spacing fluid/intravascular volume loss)

- increase nitric oxide -> vasodilation

What is step 6 of sepsis pathophysiology?

- increase systemic inflammation

- apoptosis of lymphocytes, destruction of neutrophils -> immune dysfunction

- microvascular thrombosis

What labs are done for sepsis and septic shock?

CBC with differential, CMP, coagulation studies, ABG, lactic acid, ESR and CRP, procalcitonin, UA and urine culture, blood cultures

What will we see on a CBC with differential in sepsis/septic shock?

- leukocytosis, leukopenia, left shift

- thrombocytopenia

What will we see on a CMP in sepsis/septic shock?

elevated creatinine and bilirubin

What will we see on coagulation studies in sepsis/septic shock?

elevated INR and aPTT

What will we see on a ABG in sepsis/septic shock?

reduced PaO2/FiO2 ratio

What will we see of lactic acid in sepsis/septic shock?

elevated lactic acid

What will we see of ESR and CRP in sepsis/septic shock?

elevated

What will we see of procalcitonin in sepsis/septic shock?

commonly elevated in bacterial processes

How do blood cultures work in sepsis/septick shock diagnosis?

- must use 2 different sites

- usually 48hr sensitivities if positive

- redraw if positive -> confirm clearance of bacteremia

What are the main diagnostic imaging methods used in sepsis/septic shock?

CXR, CT abdomen/pelvis, echo (TTE first, then TEE if TTE negative)

What are other diagnostic imaging methods used in sepsis/septic shock?

arthrocentesis, lumbar puncture, stool culture/PCR (diarrhea), wound cultures

When do we do a chest CT in sepsis/septic shock diagnosis?

consider if CXR is unrevealing and still highly suspicious of pulmonary source

What may be seen on a CT abdomen/pelvis in someone with sepsis/septic shock?

intraabdominal abscess, perforation, pyelonephritis

What may be seen on an echo in someone with sepsis/septic shock?

- evaluate for infective endocarditis (where vegetations are visualized)

- unexplained bacteremia or presistent bacteremia

What are we looking for when detecting and diagnosing sepsis?

new organ dysfunction due to an infection