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Infectious Disease Emergencies
Jon McCullers, MD
Chair, Department of Pediatrics
University of Tennessee Health Science Center
Pediatrician‐in Chief
Le Bonheur Children’s Hospital
I have no conflicts of interest to disclose
Objectives
Recognize common pathways that may lead to poor outcomes without intervention
Review selected presentations of infectious diseases that may be regarded as emergent
Discuss empiric treatment recommendations for infectious disease emergencies
Common pathways
Terminal events from infectious processes tend to have common final pathways
Systemic:
‐ Sepsis with shock and its complications including disseminated intravascular coagulation, myocardial dysfunction, acute respiratory distress syndrome, and multisystem organ dysfunction syndrome
Local:
‐ Brain herniation
‐ Toxin effects on the heart or lungs
‐ Pulmonary or GI hemorrhage
‐ Airway obstruction
Rapidly fatal infections
CNS: meningitis, encephalitis, subdural empyema
Sepsis: numerous bacteria, rickettsial diseases, toxic shock syndrome
Cardiac: myocarditis (e.g., viral), cardiogenic shock (e.g., diptheria
toxin)
Pulmonary: ARDS (e.g., avian influenza, hantavirus), pulmonary hemorrhage (e.g., TB, Aspergillus), obstruction (e.g., epiglottitis) GI: GI hemorrhage (e.g., Typhoid, ebola)
Pathogen – immunity balance
Infectious agents
and their toxins
Host defenses; barriers plus immunity
Unfavorable Host Factors
Increasing age
Breakdown of barriers
Diabetes
Cancer
Co‐infections (e.g., HIV)
Asplenia
End‐organ disease
Immunosuppressive agents
Management
Resuscitation / support
Timely diagnostics
Antibiotics (timing, choice)
Surgery / interventional radiology
Reduction of immunosuppression
Adjunctive therapies (e.g., IVIG)
Mild disease
Moderate disease
Severe disease
Death
Adapted from: Nicolasora N and Kaul DR, Med Clin N Am 2008;92:427‐41. Case vignette
12 yo boy presents to PCP with 2 day history of fever, runny nose, and headache
Reported a fall 3 days prior
Treated with PO antibiotics
Case vignette
12 yo boy presents to PCP with 2 day history of fever, runny nose, and headache
Reported a fall 3 days prior
Treated with PO antibiotics
Over the next 4 days developed left leg pain, then left leg weakness, then left arm weakness
Presented to the ED with labs:
WBC = 24.9 (86% segmented neutrophils)
ESR = 104, CRP = 14.1
Normal CXR
Case vignette
CT scan: extra‐axial fluid collection on the cortical surface of the right frontal lobe
Case vignette
CT scan: extra‐axial fluid collection on the cortical surface of the right frontal lobe
Treated with broad‐spectrum antibiotics, dexamethasone, and surgical drainage
Recovered and discharged without residual neurological deficits
Amadhi AM, et al., Int J Clin Surg Adv, 2014; 2(4):34‐9. Intracranial subdural empyema
Uncommon but deadly neurosurgical emergency; represents about 20% of admissions for intracranial infections
Collection of pus in the potential space between the dura and the arachnoid
Intracranial subdural empyema
Uncommon but deadly neurosurgical emergency; represents about 20% of admissions for intracranial infections
Collection of pus in the potential space between the dura and the arachnoid
Biology‐forums.com Intracranial subdural empyema
Uncommon but deadly neurosurgical emergency; represents about 20% of admissions for intracranial infections
Collection of pus in the potential space between the dura and the arachnoid
Incidence of 1/10,000 cases of otitis media in pre‐antibiotic era
M>F, most cases in 2nd or 3rd decade of life with mean age ~ 15 years
Typical pathogenesis in modern era is extension from paranasal
sinuses (67%), with meningitis (10%), otitis (9%), and trauma (8%) less common presentations
Intracranial subdural empyema
Clinical features (> 2/3 of cases):
Fever Headache
Cranial pain
Meningeal irritation
Focal neurologic signs
Depressed CNS – rapidly progressive
Seizures, generalized or focal (~ %50 of cases)
Intracranial subdural empyema
Diagnosis:
MRI is preferred modality
Identifies empyemas earlier and smaller
Identifies at base of brain and posterior fossa
CT with contrast
Most common exam in most published series
Avoid LP if diagnosis is suspected
Papilledema only ~ 50% of cases
Culture at time of surgical intervention
Typically polymicrobial
Anaerobes common (33‐67%)
Streptococci in 15‐50%, Staphylococcus in 10‐15%, Gram‐negatives in 3‐5%
Intracranial subdural empyema
Treatment:
Typically combined medical‐surgical
Urgent neurosurgical consult for drainage
In era of more frequent MRI, smaller empyemas
may receive medical treatment alone
Burr holes vs. craniectomy vs. craniotomy depending on size
Broad‐spectrum antibiotics
Meropenem and vancomycin
‐or‐ Ceftriaxone and clindamycin
Intracranial subdural empyema
Outcomes:
Rapidly progressive spread of infection to entire cerebral hemisphere, with increasing obtundation, coma, worsening focal signs, and herniation within 24‐48 hours
Intracranial subdural empyema
Outcomes:
Rapidly progressive spread of infection to entire cerebral hemisphere, with increasing obtundation, coma, worsening focal signs, and herniation within 24‐48 hours
Mortality 100% in pre‐antibiotic era, 20‐40% in early CT era, estimated 10‐20% now
Mortality higher if presentation includes coma
Outcomes better with earlier intervention and more extensive surgery
Permanent neurologic complications in 10‐44% of cases
Case vignette
17 year old student presented to the emergency room at an outside hospital with malaise, low‐grade fever, and a purplish discoloration on his face which developed during trip to ER
Temp 101.3, HR 126, RR 32, BP 90/44
Blood cultures drawn, given ceftriaxone, a NS bolus, and started on dopamine
Case vignette
17 year old student presented to the emergency room at an outside hospital with malaise, low‐grade fever, and a purplish discoloration on his face which developed during trip to ER
Temp 101.3, HR 126, RR 32, BP 90/44
Blood cultures drawn, given ceftriaxone, a NS bolus, and started on dopamine
During transfer to tertiary care hospital, BP dropped to 50 mm Hg / palpable
Stabilized in ED with dopamine / norepinephrine, 4 units O negative blood, Penicillin G, IV calcium chloride, and solumedrol
Case vignette
Physical Exam:
General: Plethoric male with generalized purpura
HEENT: Edematous eyelids, swollen shut, the entire face was purpuric.
Lungs: Intubated with clear and equal breath sounds
Cardiac: Tachycardia
Abdomen: Firm, distended, and diminished bowel sounds, purpuric skin lesions
Extremities: Mild diffuse edema and purpuric
discoloration Neuro: Nonresponsive with occasional spontaneous movements
Case vignette
Physical Exam:
General: Plethoric male with generalized purpura
HEENT: Edematous eyelids, swollen shut, the entire face was purpuric.
Lungs: Intubated with clear and equal breath sounds
Cardiac: Tachycardia
Abdomen: Firm, distended, and diminished bowel sounds, purpuric skin lesions
Extremities: Mild diffuse edema and purpuric
discoloration Neuro: Nonresponsive with occasional spontaneous movements
Case vignette
WBC = 11.3 (35% neutrophils, 52% bands, neutrophils
have intracellular bacteria
visible)
HgB = 10.8
Plt = 58k
PT/PTT = 18.1 / 87.9
Creatinine = 3.6
Glucose = 51
Case vignette
Hospital Course:
Moved to the ICU. Given Pen G and ceftriaxone with mechanical ventilation and support for DIC and persistent hypotension
Expired 18 hours after presentation to outside hospital
Final diagnosis: meningococcemia with Waterhouse‐Friderichsen
Syndrome (adrenal failure due to hemorrhage into adrenal glands)
Aronica P, et al., Clin Micro, 1996; online case of the month. Meningococcemia
The Disease Which Raged During the Spring of 1805
‐ Gaspard Vieusseux
“It commences suddenly with prostration of strength, often extreme: the face is distorted, the pulse feeble. There appears a violent pain in the head, especially over the forehead; then there comes pain of the heart or vomiting of greenish material, stiffness of the spine, and in infants, convulsions. In cases which were fatal, loss of consciousness occurred. The course of the disease is very rapid, termination by death or by cure. In most of the patients who died in 24 hours or a little after, the body is covered with purple spots at the moment of death or very little time afterward.”
Meningococcemia
Meningococcal disease peaks during winter (Nov – Feb)
Incidence is inverse to age; about 50% of cases are in kids < 2 years
Most epidemic disease occurs in older children and young adults
Serotypes B and C account for 45% each of disease in the US; MCV4 covers A, C, W135, and Y, but not B (2 doses at ages 11‐12 and age 16)
Serotype B vaccine approved by FDA in November but not incorporated into routine schedules yet
Meningococcemia
Clinical manifestations:
Rash
Fever
Vomiting
Headache
Lethargy Shock
90+%
80%
50%
40%
40%
40%
Meningococcemia
Clinical manifestations:
Rash
Fever
Vomiting
Headache
Lethargy Shock
90+%
80%
50%
40%
40%
40%
Rash: typically begins as petechiae (recognized in 50‐60%) which coalesce together to form ecchymotic, purpuric lesions over a period of hours. However, 10‐15% have non‐classic maculopapular rash similar to many viral exanthems, and some have no rash at all
Meningococcemia
Common laboratory findings:
Leukopenia
Thrombocytopenia
Coagulation defects
Elevated LFTs
Acidosis
Meningococcemia
Common laboratory findings:
Leukopenia
Thrombocytopenia
Coagulation defects
Elevated LFTs
Acidosis
Diagnosis: gram stain and culture from a sterile site
Meningococcemia
Common laboratory findings:
Leukopenia
Thrombocytopenia
Coagulation defects
Elevated LFTs
Acidosis
Diagnosis: gram stain and culture from a sterile site
Treatment: Ceftriaxone (or Pen G if susceptible strain) Steroids for Waterhouse‐Friderichsen Syndrome but not otherwise
Case vignette
Previously healthy 8 year old boy presents for infection of his left thigh
Had a minor cat scratch on his leg 10 days prior. Five days later he had some swelling and tenderness at the site with a limp. Saw his PCP and was prescribed amoxicillin and prednisone. No history of trauma. Seen a second time two days later at an outside emergency room and diagnosed as cellulitis. Antibiotic changed to cephalexin.
Case vignette
Previously healthy 8 year old boy presents for infection of his left thigh
Had a minor cat scratch on his leg 10 days prior. Five days later he had some swelling and tenderness at the site with a limp. Saw his PCP and was prescribed amoxicillin and prednisone. No history of trauma. Seen a second time two days later at an outside emergency room and diagnosed as cellulitis. Antibiotic changed to cephalexin.
At presentation in the ED: Temp = 39.9, HR = 130, RR = 50, BP = 80/50, toxic appearing
Case vignette
Examination of the left thigh revealed extensive swelling, induration
and edema with dusky skin, blistering and bleb formation, in addition to an area of gangrenous skin
Abass et al. Cases Journal 2008 1:228.
Case vignette
WBC = 22.4 (76% neutrophils, 18% bands)
HgB = 9.3
Platelets = 70k
ESR = 75, CRP = 33.2
PT/PTT = 19.5 / 89.0; AST/ALT = 456 / 224
CPK = 1231
Case vignette
Patient was started on dopamine and dobutamine after several fluid boluses and received multiple transfusions of FFP
MRI showed swelling and extension of inflammation along fascia planes
Surgical consultation led to emergent
debridement of all necrotic tissues, and drainage of involved fascia planes via extensive fasciotomy
Case vignette
Blood cultures grew Group A Streptococcus, as did wound cultures from surgery
Histopathologic examination of tissues confirmed a diagnosis of necrotizing fasciitis
Patient recovered after three days in the ICU and received a total of 21 days of penicillin and clindamycin
Abass K, et al., Cases Journal, 1(8):228. Necrotizing fasciitis
About 10,000 cases per year in the US
Typically arises from a break in the skin such as a scratch or minor trauma
Group A Streptococcus is responsible for most cases, with Staphylococcus aureus second; often polymicrobial with anaerobes present
Necrotizing fasciitis
Clinical signs and symptoms:
Typically starts as an ordinary cellulitis, however pain is out of proportion to exam findings and it progresses extremely rapidly despite appropriate antibiotic therapy
Induration often extends beyond area of erythema, and tissue becomes dusky due to poor perfusion
Blebs, bullae, and areas of frank necrosis are common
Sometime accompanied by systemic illness including edema, proteinuria, and hypocalcemia
Necrotizing fasciitis
Treatment is surgical with extensive excision and debridement of affected tissue and healthy tissue at the margins
Antibiotic therapy and supportive care are adjuncts to surgery; therapy can be guided by gram stain and culture but should cover MRSA and anaerobes (e.g., Penicillin G, clindamycin (Eagle effect), and ceftriaxone)
Mortality is high – 25‐50% in many series
Case vignette
Healthy 13 year old athlete; complained of sore throat, fever, and cough 9/1/09
Started on azithromycin and oseltamivir morning of 9/2/09 by private physician
Went to LB Emergency Room evening of 9/2/09 with chest pain, O2 sat 99% on room air
Case vignette
Rapid deterioration in ER, intubated, sent to PICU, treated with vancomycin, meropenem, azithromycin, and oseltamivir
Progressed to high frequency oscillating ventilator then extracorporeal membrane oxygenation (ECMO) but died 4 days later
(+) 2009 H1N1 influenza; methicillin‐resistant Staphylococcus aureus (MRSA) from ET tube
Necrotizing, hemorrhagic pneumonia on autopsy
Secondary bacterial pneumonia
History
‐ R.T.H. Laennec was the first to describe secondary bacterial infections following influenza
‐ He noted that the prevalence of pneumonia increased during an epidemic of “la grippe” in 1803 in Paris
‐ Today it is well‐appreciated that many influenza‐
related deaths are due to secondary invaders such as Streptococcus pneumoniae and Staphylococcus aureus
Laennec, R. T. H. 1923., p. 88‐95. In Translation of selected passages from De l'Auscultation Mediate. Secondary bacterial pneumonia
In pandemics
‐ It is estimated that 95% of all deaths during the 1918 pandemic were complicated by secondary bacterial pneumonia
(primarily S. pneumoniae)
‐ Estimated at 50‐70% in 1957 and 1968
‐ This has been a key concern for pandemic planning
‐ The emergence of the novel pandemic H1N1 strain led to increased opportunities to study the epidemiology and pathogenesis of secondary bacterial infections following influenza
Morens DM, et al., J Infect Dis 2008;198:962‐70.
McCullers JA. J Infect Dis 2009;198:945‐7.
Secondary bacterial pneumonia
2009 pandemic H1N1
‐ Few reports of bacterial superinfections in initial descriptions of severe pandemic related disease
‐ However, most critically ill patients were treated with broad spectrum antibiotics, and invasive assays (e.g., pleural taps) were not commonly done
‐ Thorough evaluations of severe and fatal cases show 25‐56% had evidence of bacterial super‐infection (S. pneumoniae, S. aureus, S. pyogenes), with 14‐46% mortality
‐ 5 deaths in Memphis from S. aureus super‐infections with H1N1
Dominguez‐Cherit G, et al. JAMA 2009;302:1880‐7. Gill JR, et al., Arch Pathol Lab Med 2010;134:235‐43.
CDC. MMWR 2009;58(38):1071‐4. Mauad T, et al., Am J Respir Crit Care Med 2010;181:72‐9. Esstensoro E, et al., Am J Respir Crit Care Med 2010, doi:10.1164/201001‐0037OC.
Treatment of pneumonia during co‐infection
‐ High mortality of secondary bacterial pneumonia during 2009 H1N1 pandemic despite “appropriate” antibiotic use in 95‐99% of reported cases
‐ The influenza anti‐viral NAI oseltamivir delays onset and reduces severity of secondary bacterial pneumonia clinically and in our mouse model ‐ Ampicillin therapy can eliminate bacteria in mouse model, but does not prevent mortality
‐ Combined therapy with oseltamivir and ampicillin had the best outcomes in our mouse model
McCullers JA. J Infect Dis 2004;190:519‐26.
Antibiotics in the Mouse Model n = 17 / group PR8 25 TCID50
S. pneumoniae 200 CFU Ampicillin 100 mg/kg q12 x 5d
Ghoneim H and McCullers JA, J Infect Dis 2013, doi: 10.1093/infdis/jit653
Antibiotics in the Mouse Model Ampicillin treatment eliminates bacteria rapidly
n = 17 / group PR8 25 TCID50
S. pneumoniae 200 CFU Ampicillin 100 mg/kg q12 x 5d
Ghoneim H and McCullers JA, J Infect Dis 2013, doi: 10.1093/infdis/jit653
Antibiotics in the Mouse Model Ampicillin treatment eliminates bacteria rapidly, but is ineffective at preventing mortality
n = 17 / group PR8 25 TCID50
S. pneumoniae 200 CFU Ampicillin 100 mg/kg q12 x 5d
Ghoneim H and McCullers JA, J Infect Dis 2013, doi: 10.1093/infdis/jit653
Mild vs. Severe Pneumonia
Ampicillin treatment has no effect on mortality if treatment begins once pneumonia is severe and bacterial burden is high
n = 17 / group PR8 25 TCID50
S. pneumoniae 200 CFU Ampicillin 100 mg/kg q12 x 5d
Ghoneim H and McCullers JA, J Infect Dis 2013, doi: 10.1093/infdis/jit653
“Anti‐inflammatory” antibiotics
p < 0.05 by log rank test compared to all other groups
‐ Azithromycin, which also has anti‐inflammatory effects, performs best in the model
Karlström ÅN et al., J Infect Dis 2009;199(3):311‐9.
Secondary bacterial pneumonia
Clinical guidelines for community‐acquired pneumonia:
Hospitalize :
Children < 6 months of age
Moderate to severe CAP (hypoxemia, respiratory distress)
Suspected resistant or virulent organism (e.g., MRSA)
Concern over outpatient therapy or follow‐up
IDSA Guidelines, Clin Infect Dis. (2011) 53 (7): e25‐e76.
Secondary bacterial pneumonia
Clinical guidelines for community‐acquired pneumonia:
Hospitalize :
Children < 6 months of age
Moderate to severe CAP (hypoxemia, respiratory distress)
Suspected resistant or virulent organism (e.g., MRSA)
Concern over outpatient therapy or follow‐up
Diagnostics:
Pulse oximetry in all children
Do test for respiratory viruses
Blood cultures, sputum, urine antigen not recommended
Test for atypical pathogens when clinically indicated
CBC not useful; CRP useful only if hospitalized
CXR (PA and lateral) only if meets criteria for hospitalization
IDSA Guidelines, Clin Infect Dis. (2011) 53 (7): e25‐e76.
Secondary bacterial pneumonia
Clinical guidelines for community‐acquired pneumonia:
Treatment:
Treatment not routine for pre‐school children
Amoxicillin (outpatient) or ampicillin (inpatient) is first‐line
Immunized patients
Alter only if resistant organism suspected based on
patient or local susceptibilities
Early therapy with oseltamivir for all influenza
Treat viral‐bacterial co‐infections with oseltamivir and appropriate antibiotics
Macrolide therapy in older children with atypical pneumonia
IDSA Guidelines, Clin Infect Dis. (2011) 53 (7): e25‐e76.
Case vignette
10 yo F with ALL in induction presents with 2 hour history of Fever to 39 in the Target House; ANC = 0
Admitted and placed on cefepime
Case vignette
10 yo F with ALL in induction presents with 2 hour history of fever to 39 in the Target House; ANC = 0
Admitted and placed on cefepime
12 hours later complains of headache and malaise; PE is normal
Vancomycin is added to her therapy
Progressive obtundation; transfer to ICU
Generalized seizures
CT shows edema, hydrocephalus
Emergency shunt placed and intrathecal vancomycin started
Case vignette
CSF exam: WBC 60; RBC 0
Protein 112; Glucose 235
Gram stain: numerous filamented
gram‐positive rods
Bacillus cereus
Therapy changed to meropenem
with rapid clearance of CSF
Case vignette
CSF exam: WBC 60; RBC 0
Protein 112; Glucose 235
Gram stain: numerous filamented
gram‐positive rods
Bacillus cereus
Therapy changed to meropenem
with rapid clearance of CSF
Remained in a coma for a year
Leukemia went into spontaneous remission with infection
Woke up one day, went through several years rehab, walked the St. Jude marathon
Neutropenia and Fever
Phagocytic theory of immunity:
1872: Felix Birch‐Hirschfeld demonstrates that bacteria injected into the blood are found within leukocytes
1874: Danish pathologist Peter Panum hypothesizes that leukocytes kill invading bacteria
1884: Elie Metchnikoff coins the term phagocytosis to describe the process by which leukocytes ingest bacteria
1966: Gerald Bodey describes the relationship between ANC and infection in neutropenic patients‐ breakpoints of 1000, 500, and 100 established
Bullock W, The History of Bacteriology, 1979;259.
Bodey GP, et al., Ann Intern Med 1966;64:328‐40.
Neutropenia and Fever
History of empiric therapy of Neutropenia and Fever
1971: Schimpff shows that therapy with carbenicillin and gentamicin administered before infection was identified was effective at reducing mortality from Pseudomonas aeruginosa
Acceptance of this approach led to significant decreases in incidence of infections and mortality from gram‐negative organisms in cancer patients in the 1970s
Proportion of infections caused by gram‐negative organisms changes from ~2/3 between 1977‐1985 to ~1/3 between 1986 and 1995
Schimpff S et al., N Engl J Med 1971;284:1061‐5.
Bodey GP et al., Cancer 1978;41:1610‐22.
Neutropenia and Fever
Survival from childhood leukemia
SJ “Total Therapy” studies
I‐IV
V‐IX
X‐XII
XIII‐XVI
1962‐66 Combination chemo
1967‐79 CNS “prophylaxis” XRT and IT methotrexate
1979‐91 Early intensification, high dose methotrexate
1991‐present Reinduction, intensification of IT, pulsed Dex
Pui CH et al., N Engl J Med 1998;339:605‐15.
SJ “Total Therapy” studies
I‐IV
V‐IX
X
XI
XII
1962‐66 3.7% infectious mortality during induction
1967‐79 0.93% with total WBC kept > 1000
1979‐83 0.61% with WBC > 2500, ANC and ALC > 500
1983‐88 1.7% with intensification and frequent neutropenia
1988‐91 0/182 patients with standardized empiric therapy
Pui CH et al., N Engl J Med 1998;339:605‐15.
Neutropenia and Fever
Agents causing bacteremia in neutropenic patients
Gram‐positives (55%)
Coagulase‐negative staphylococci (20)
Viridans streptococci (17)
Staphylococcus aureus (13)
Others (5)
Gram‐negatives (43%)
Escherichia coli (18)
Pseudomonas aeruginosa (10)
Klebsiella spp. (5)
Enterobacter spp. (3)
Others (7)
Anaerobes (2%)
Bacillus cereus
Bacillus spp.
Clostridium spp.
McCullers JA & Shenep JL, In: Immunocompromised
infants and children (Patrick CC, Ed.) 2001;353‐87.
Neutropenia and Fever
Current guidelines for children:
Risk assessment at presentation should help guide management
Disease, chemotherapy, absolute neutrophil count, disruption of barriers, patient’s history
If in doubt, consider high‐risk
ANC < 500 is commonly used breakpoint
Neutropenia and Fever
Current guidelines for children:
Risk assessment at presentation should help guide management
Disease, chemotherapy, absolute neutrophil count, disruption of barriers, patient’s history
If in doubt, consider high‐risk
ANC < 500 is commonly used breakpoint
Obtain blood cultures from all lumens of any central venous catheter
Consider peripheral cultures (but never delay therapy)
Consider urine culture
CXR only if symptomatic
Neutropenia and Fever
Initiate empiric antimicrobial therapy emergently
Single best predictor of outcomes
Anti‐pseudomonal beta‐lactam is first line therapy (e.g., cefepime)
Consider adding vancomycin if risk factors
Consider adding aminoglycoside if risk factors
Admit for inpatient observation
In controlled settings with appropriate infrastructure, can consider outpatient therapy for low‐risk patients
Oral therapy for low‐risk patients remains experimental in children
Neutropenia and Fever
Clinical pearls from the case vignette
Reassessment and alteration of therapy when indicated is critical
Clinical signs beyond fever are often not present
Identification of the organism is paramount
Never give up hope!
Questions?