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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?