Acute Epiglottitis in the Immunocompromised Host: Case Report and Review of the Literature

Acute Epiglottitis in the Immunocompromised Host: Case Report and Review of the Literature Open Forum Infectious Diseases REVIEW ARTICLE Acute Epiglottitis in the Immunocompromised Host: Case Report and Review of the Literature 1 2 3 4 5 Cheng Chen, Mukil Natarajan, David Bianchi, Georg Aue, and John H. Powers 1 2 University of Cambridge, Cambridge, United Kingdom; Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, 3 4 National Institutes of Health, Bethesda, Maryland; National Institute on Deafness and Communication Disorders, National Institutes of Health, Bethesda, Maryland; Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., NCI Campus at Frederick, Frederick, Maryland We present a case of acute epiglottitis in a 16-year-old with severe aplastic anemia. He was admitted with a history suggestive of a severe upper airway infection and an absolute neutrophil count of 0 per cubic millimeter. Despite his immunocompromised state, he presented with the classical signs and symptoms of epiglottitis. We review here the presentation and comorbidities of immuno- compromised patients with epiglottitis. In addition, the appropriate choice of empirical antibiotic therapy is important for the man- agement of epiglottitis in immunocompromised patients, especially in the post–Haemophilus inu fl enza type B vaccination era. In our patient, Enterobacter cloacae was isolated from endoscopically directed throat cultures, and treatment was successful without the need for intubation. e Th current literature suggests that in immunocompromised patients, particularly those who are neutropenic, there is a potentially wide range of organisms, both bacterial and fungal, that may play a role in the pathology of acute epiglottitis. Keywords. aplastic anemia; Enterobacter cloacae; epiglottitis; immunocompromise; malignancy; neutropenia. Epiglottitis is a life-threatening condition, characterized by here a case of acute epiglottitis with Enterobacter cloacae in a acute inflammation of the supraglottic region of the orophar - 16-year-old male with severe aplastic anemia with a review of ynx, with the potential risk of fatal airway obstruction. Effective the literature, exploring the clinical presentation, outcomes, and management requires rapid diagnosis, airway management, and microbial etiologies in immunocompromised patients. treatment of the causative agent. Epiglottitis is an inflamma- CASE REPORT tory disease, yet it still occurs in patients whose inflammatory responses are blunted by neutropenia and immunocompro- A 16-year-old Jamaican male presented to his local hospital mised patients. Although these patients are known to be more with fatigue, epistaxis, and dyspnea. He had no significant past susceptible to infections, it has yet to be demonstrated whether medical history or family history of serious medical illness. epiglottitis in immunocompromised patients presents differently Initial blood tests showed a white cell count of 1900 per cubic or follows a different clinical course. Previously, 75%–90% of millimeter (absolute neutrophil count 90 per cubic millimeter), cases of epiglottitis were caused by Haemophilus inu fl enza type hemoglobin 5.3  g per deciliter, and platelets 36 000 per cubic B (Hib). Vaccination, introduced in 1985, significantly reduced millimeter. He was hospitalized 3 months later, and bone mar- the incidence of epiglottitis [1]. Cases presenting today show a row biopsy performed 1  month into the admission was con- mixed microbial etiology, with a relative increased incidence in sistent with aplastic anemia. He was discharged after receiving older children [2]. Epiglottitis in immunocompromised patients packed red blood cells, pooled platelet transfusions, and intra- may be caused by a wider variety of organisms than epiglotti- venous antibiotics of unknown type, dose, and duration. tis in immunocompetent children and adolescents. We present Five months aer ini ft tial presentation, he was admitted to the US National Institute of Health Clinical Center with a 1-week history of fever, dysphagia, odynophagia, cough, and Received 4 December 2017; editorial decision 9 February 2018; accepted 14 February 2018. scant hemoptysis. He was enrolled in an institutional review Correspondence: J.  H. Powers  III, MD, Clinical Research Directorate/Clinical Monitoring board–approved clinical research protocol, and informed con- Research Program, Leidos Biomedical Research, Inc., NCI Campus at Frederick, 5601 Fishers Lane, Room 4D50, Bethesda, MD 20892 (john.powers@nih.gov). sent was obtained and documented. On examination, his body Open Forum Infectious Diseases temperature was 38.2 C, blood pressure 126/91 mm Hg, heart © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases rate 88 beats per minute, respiratory rate 18 breaths per min- Society of America. This is an Open Access article distributed under the terms of the Creative ute, and oxygen saturation 98% breathing ambient room air. He Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any appeared thin and lethargic, but was not in acute distress, and medium, provided the original work is not altered or transformed in any way, and that the work was spitting blood-tinged saliva into a cup. He denied dyspnea is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofy038 and was phonating normally. He was tender diffusely around Epiglottitis in the Immunocompromised • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/3/ofy038/4868583 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Figure  1. Topogram and sagittal view of the neck on computerized tomography scan performed on the day of presentation showing classic “thumbprint” sign due to swelling of epiglottis. the neck. er Th e were no other abnormal examination findings. right tonsillar area isolated Enterobacter cloacae resistant to cefa- His laboratory findings showed a white cell count of 1430 per zolin, cefoxitin, ceftazidime, ceftriaxone, co-amoxiclav, ampi- cubic millimeter (absolute neutrophil count 0 per cubic mil- cillin, aztreonam, and piperacillin/tazobactam; subsequently, limeter), hemoglobin 10.7  g per deciliter, and platelets 33 000 he was prescribed meropenem (750  mg, every 8 hours). He per cubic millimeter. Radiographic imaging showed a classic clinically improved with this antibiotic regimen, and follow-up “thumbprint” sign at the site of the epiglottis (Figure 1). Direct laryngoscopy 17 days later showed significant improvement in laryngoscopy showed an erythematous, enlarged, and pos- the appearance of the epiglottis (Figure 3). teriorly ptotic epiglottis that was not necrotic (Figure  2). e Th patient immediately received intravenous piperacillin/tazo- DISCUSSION bactam (3.375 g, every 6 hours), vancomycin (400 mg, every 6 Epiglottitis is a medical emergency, with the potential serious hours), and micafungin (100 mg, once daily), as well as intrave- complication of airway compromise secondary to the inflam- nous dexamethasone (4 mg, every 6 hours) and nebulized race- matory response to infection in the upper airway. It is a clinical mic epinephrine (0.5 mL of 2.25%, every 6 hours). He clinically diagnosis characterized by odynophagia, stridor, drooling, and improved while being closely monitored in the intensive care a “hot potato” voice. The patient may also show signs of sep- unit; there was no need for definitive airway management by sis in cases of severe infection. Direct fibreoptic laryngoscopy intubation. Blood cultures showed no growth, but endoscop- shows an inflamed and swollen epiglottis; however, examination ically directed cultures from directly observed exudate on the should be done with caution as it can lead to rapid airway com- promise. Radiology, including lateral x-ray of the cervical spine or computerized tomography, may aid in diagnosis by showing a classic “thumbprint sign,” evidence of soft tissue swelling of the epiglottis. While antimicrobials are part of treatment, additional support, including steroids [3], is used to reduce the inflamma- tion, and intubation/tracheostomy under carefully monitored conditions maintains the collapsing airway. In cases where there is abscess formation, surgical debridement may also be neces- sary. Isolated necrosis of the epiglottis also can occur [29]. Demographics of Epiglottitis in the Immunocompromised We performed a literature search evaluating epiglottitis in the immunocompromised host, which yielded 48 published cases from 34 published reports (Table 1) [4–37 ]. Patient ages ranged from 4 months to 70 years, with a mean age of 35.5 years, with 23 male and 25 female patients. Twenty-four had immuno- compromise secondary to cancer and/or chemotherapy, and 12 patients were positive for HIV. The remainder had a variety of causes of immunocompromise, including Epstein-Barr virus Figure 2. Laryngoscopy image of epiglottis showing erythematous and enlarged epiglottis. (EBV) mononucleosis, renal transplantation, and drug-induced 2 • OFID • Chen et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/3/ofy038/4868583 by Ed 'DeepDyve' Gillespie user on 16 March 2018 In our patient, there was no stridor or pus on laryngoscopy. Neutrophils are the key effector cells of the innate immune system, so when patients become neutropenic (<500 per cubic millimeter), they become susceptible to infections. Sore throat due to mucositis may be common in patients receiving chemo- therapy for malignancy, but there should be a high index of suspicion if symptoms worsen or progress to include difficulty swallowing, clearing secretions, or breathing. We postulate that there are 3 reasons why, despite the ongoing inflammation and medical intervention, this patient’s airway remained competent without any need for airway support. First is that, anatomic- ally, this 16-year-old’s head and neck anatomy may be different compared with younger children with Hib epiglottitis. There is more space for the swelling to expand before impinging on the airway. Second, there is an inverse correlation between patient age and risk of laryngospasm [38]. Third, the severity of his immunocompromise from aplastic anemia may have limited Figure 3. Follow-up laryngoscopy image showing significant improvement in ery- the extent of host response, thereby presenting a lower-than-ex- thema and swelling. pected degree of inflammation and swelling. Clinical Course, Treatment, and Outcomes of Epiglottitis in the neutropenia (see the footnote to Table 1). Of these 48 patients, Immunocompromised 18 were neutropenic, defined by an absolute neutrophil count The majority of cases were empirically treated initially with and/or total white cell count of less than 1000 per cubic millim- broad-spectrum antibiotics. Of the 21 patients in whom fun- eter. The range of underlying causes of immunocompromise in gal organisms were isolated, 7 empirically received antifungal neutropenic patients was similar to that in non-neutropenics. agents, including 2 patients with concomitant neutropenia. Clinical Presentation of Epiglottitis in the Immunocompromised As many of the organisms isolated are part of the normal oro- Epiglottitis has previously been reported in 1 other patient pharyngeal flora, especially Candida sp, their role in infection vs with aplastic anemia [12]. Our patient presented with typical colonization often is unclear. The benefits or harms of adminis- signs and symptoms of epiglottitis similar to those observed in tering antifungals empirically are unclear from this case series. immunocompetent patients. Specifically, in the reviewed case Prognosis of Epiglottitis in the Immunocompromised reports of immunocompromised patients, patients presented Of the 48 case reports, 13 people died and 35 survived (27% with symptoms of respiratory distress, stridor, fever, drooling, overall mortality), highlighting the life-threatening nature of sore throat, odynophagia, and dysphagia [4–37]. epiglottitis. Of the neutropenic patients, 6 died and 12 survived, giving a slightly higher mortality of 33% (Table  1). Two of 3 patients with tongue involvement were neutropenic. Table  1. Demographics of Epiglottitis in the Immunocompromised Table  2 shows the interventions used in addition to anti- According to 48 Cases from Published Studies [4–37] microbial agents and their associated mortalities in the patients Demographic Data for Cases who received them. Mean age (SD, range), y 35.5 (20.1, 4 mo–70 y) It is not possible to determine the effects of various interven- Sex Male 23 48% tions on mortality from this case series. Intubation and trache- Female 25 52% ostomy may be used in more severe cases, so higher mortality Underlying condition Malignancy 24 50% with these interventions may reflect higher baseline risk of HIV 12 25% death independent of the interventions administered. Other 12 25% Neutropenia ANC or WBC <1000 18 38% Organisms Isolated in Immunocompromised Patients Mortality Neutropenic 33% In 29 patients, a single organism was isolated from cultures of the Not neutropenic 23% throat, sputum, blood, or tissue biopsy (either from an isolated Abbreviations: ANC, absolute neutrophil count; WBC, total white blood cell count. site or from multiple sites), while 3 patients had either no growth Other causes of immunocompromise included Epstein-Barr virus (EBV) mononucleosis in pregnancy, bone marrow aplasia of unknown origin, hypocellular bone marrow of on cultures or they were not done. The remaining 16 patients unknown origin, aplastic anemia, virus-associated hemophagocytic syndrome secondary grew multiple organisms. A summary of organisms is shown in to EBV infection, renal transplantation, procainamide-induced neutropenia, infection-re- lated hemophagocytic lymphohistiocytosis, Cytomegalovirus-related pancytopenia, sys- Table  3. The most frequent organism isolated from either cul- temic lupus erythematosus, and drug-induced agranulocytosis. In 1 patient, the cause of immunocompromise was not documented. tures or biopsy was Candida spp, followed by Streptococcus spp. Epiglottitis in the Immunocompromised • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/3/ofy038/4868583 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Supportive Treatments Used in Addition to Antimicrobial Therapy rod-shaped organism oen f ft ound in the normal flora of the in the 48 Published Cases of Epiglottitis in the Immunocompromised [4–37] gastrointestinal tract [39]. It is also a nosocomial pathogen, with previous documentations of E.  cloacae outbreaks [40]. Supportive Treatment No. Mortality, % Flynn et al. suggested that Enterobacter from patients’ endogen- Intubation 30 37 ous flora can be the source of “nosocomial” Enterobacter infec- Tracheostomy 10 40 tion [41]. Our patient did recently have a hospital admission Steroids 9 33 in Jamaica and receipt of prior antibiotics, so it is unclear Granulocyte stimulating factor 5 20 whether the source of his infection was nosocomial or com- Surgical debridement 2 0 Racemic epinephrine 2 0 munity acquired. Nonetheless, this finding has implications for the choice of empirical antimicrobial therapy for the initial management of epiglottitis in immunocompromised patients. Eight of the neutropenic patients grew Candida spp and were Gram-negative and fungal infections should be considered in subsequently treated with antifungal agents (11 of 31 non-neu- this setting. tropenic patients grew Candida spp). The organisms grown from neutropenic patients showed more variety and were less predict- CONCLUSIONS able, such as Prevotella spp and Serratia marcescens, compared In the immunocompromised patient, there should be a low with primarily Streptococcus pneumoniae and Candida albicans threshold of suspicion for diagnosing acute epiglottitis, particu- in non-neutropenic patients. In 2 patients, cultures were not larly in those who are neutropenic. The immunocompromised done, diagnosis was made on a clinical basis, and the infection state and neutropenia do not rule out diseases caused by neutro- resolved without intervention. There was 1 case where there was philic infiltration as tissue-based inflammation still may result in no growth from blood cultures, throat swabs, or tracheal aspir- disease. Epiglottitis in reported cases presents similarly in immu- ate, but the patient survived and the disease resolved after receipt nocompromised and immunocompetent patients. Early recog- of cefotaxime, erythromycin, and metronidazole. nition can allow prompt treatment, including administration of Here we report the first documented case of acute epiglot- broad-spectrum antimicrobials and perhaps antifungals, given titis associated with Enterobacter cloacae, a gram-negative the wide range of organisms isolated. The impact of broad-spec- trum antimicrobials with additional antifungals on outcome is unknown given that the organisms isolated also are part of the Table  3. Organisms Grown From 48 Cases of Epiglottitis in normal oropharyngeal flora, and whether they are colonizing or Immunocompromised Patients From Published Cases [4–37] causing infection often is unclear. Airway management is para- mount, but endotracheal intubation is not always necessary and Organism Isolated Neutropenic Total % of All Cases was not necessary in our patient. Sedation, inhalers, and racemic Candida spp 8 19 40 epinephrine should be avoided [3]. Rapid treatment with steroids Streptococcus spp 2 12 25 Staphylococcus spp 2 5 10 to reduce the immediate inflammation, along with antimicrobials Cytomegalovirus 2 5 10 to treat the underlying infection, has been associated with shorter Aspergillus spp 2 4 8 intensive care unit and overall length of hospital stay; close mon- Serratia spp 3 3 6 itoring and good nursing care are essential for the appropriate Enterococcus spp 2 2 4 management of epiglottitis in the immunocompromised patient. Corynebacterium diphtheriae 1 2 4 Escherichia coli 1 2 4 Acknowledgments Neisseria spp 1 2 4 Financial support. This project has been funded in whole or in part Prevotella spp 2 2 4 with federal funds from the National Cancer Institute, National Institutes of Pseudomonas spp 1 2 4 Health, under Contract No. HHSN261200800001E. The content of this pub- Klebsiella pneumoniae 0 1 2 lication does not necessarily reflect the views or policies of the Department Actinomyces israelii 0 1 2 of Health and Human Services, nor does mention of trade names, commer- Bacteroides spp 0 1 2 cial products, or organizations imply endorsement by the US Government. Diplococcus 0 1 2 Potential coni fl cts of interest. None of the authors have any conflict of Eikenella corrodens 1 1 2 interest related to this work. All authors have submitted the ICMJE Form Haemophilus influenzae 1 1 2 for Disclosure of Potential Conflicts of Interest. Conflicts that the editors Kingella kingae 1 1 2 consider relevant to the content of the manuscript have been disclosed. Mucormycosis 0 1 2 Stenotrophomonas maltophilia 1 1 2 References Torulopsis glabrata 0 1 2 1. Shah RK, Stocks C. Epiglottitis in the United States: national trends, variances, prognosis, and management. Laryngoscope 2010; 120:1256–62. Zygomycete 0 1 2 2. 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Am J Med 1988; 85:701–2. cloacae in a neonatal unit and review of the literature. J Hosp Infect 2008; 70:7–14. 22. Kessler HA, Schade R, Trenholme GM, et al. Acute pneumococcal epiglottitis in 41. Flynn DM, Weinstein RA, Nathan C, et al. Patients’ endogenous flora as the source immunocompromised adults. Scand J Infect Dis 1980; 12:207–10. of “nosocomial” Enterobacter in cardiac surgery. J Infect Dis 1987; 156:363–8. Epiglottitis in the Immunocompromised • OFID • 5 Downloaded from https://academic.oup.com/ofid/article-abstract/5/3/ofy038/4868583 by Ed 'DeepDyve' Gillespie user on 16 March 2018 http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Open Forum Infectious Diseases Oxford University Press

Acute Epiglottitis in the Immunocompromised Host: Case Report and Review of the Literature

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Open Forum Infectious Diseases REVIEW ARTICLE Acute Epiglottitis in the Immunocompromised Host: Case Report and Review of the Literature 1 2 3 4 5 Cheng Chen, Mukil Natarajan, David Bianchi, Georg Aue, and John H. Powers 1 2 University of Cambridge, Cambridge, United Kingdom; Fungal Pathogenesis Section, Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, 3 4 National Institutes of Health, Bethesda, Maryland; National Institute on Deafness and Communication Disorders, National Institutes of Health, Bethesda, Maryland; Hematology Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, Maryland; Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research, Inc., NCI Campus at Frederick, Frederick, Maryland We present a case of acute epiglottitis in a 16-year-old with severe aplastic anemia. He was admitted with a history suggestive of a severe upper airway infection and an absolute neutrophil count of 0 per cubic millimeter. Despite his immunocompromised state, he presented with the classical signs and symptoms of epiglottitis. We review here the presentation and comorbidities of immuno- compromised patients with epiglottitis. In addition, the appropriate choice of empirical antibiotic therapy is important for the man- agement of epiglottitis in immunocompromised patients, especially in the post–Haemophilus inu fl enza type B vaccination era. In our patient, Enterobacter cloacae was isolated from endoscopically directed throat cultures, and treatment was successful without the need for intubation. e Th current literature suggests that in immunocompromised patients, particularly those who are neutropenic, there is a potentially wide range of organisms, both bacterial and fungal, that may play a role in the pathology of acute epiglottitis. Keywords. aplastic anemia; Enterobacter cloacae; epiglottitis; immunocompromise; malignancy; neutropenia. Epiglottitis is a life-threatening condition, characterized by here a case of acute epiglottitis with Enterobacter cloacae in a acute inflammation of the supraglottic region of the orophar - 16-year-old male with severe aplastic anemia with a review of ynx, with the potential risk of fatal airway obstruction. Effective the literature, exploring the clinical presentation, outcomes, and management requires rapid diagnosis, airway management, and microbial etiologies in immunocompromised patients. treatment of the causative agent. Epiglottitis is an inflamma- CASE REPORT tory disease, yet it still occurs in patients whose inflammatory responses are blunted by neutropenia and immunocompro- A 16-year-old Jamaican male presented to his local hospital mised patients. Although these patients are known to be more with fatigue, epistaxis, and dyspnea. He had no significant past susceptible to infections, it has yet to be demonstrated whether medical history or family history of serious medical illness. epiglottitis in immunocompromised patients presents differently Initial blood tests showed a white cell count of 1900 per cubic or follows a different clinical course. Previously, 75%–90% of millimeter (absolute neutrophil count 90 per cubic millimeter), cases of epiglottitis were caused by Haemophilus inu fl enza type hemoglobin 5.3  g per deciliter, and platelets 36 000 per cubic B (Hib). Vaccination, introduced in 1985, significantly reduced millimeter. He was hospitalized 3 months later, and bone mar- the incidence of epiglottitis [1]. Cases presenting today show a row biopsy performed 1  month into the admission was con- mixed microbial etiology, with a relative increased incidence in sistent with aplastic anemia. He was discharged after receiving older children [2]. Epiglottitis in immunocompromised patients packed red blood cells, pooled platelet transfusions, and intra- may be caused by a wider variety of organisms than epiglotti- venous antibiotics of unknown type, dose, and duration. tis in immunocompetent children and adolescents. We present Five months aer ini ft tial presentation, he was admitted to the US National Institute of Health Clinical Center with a 1-week history of fever, dysphagia, odynophagia, cough, and Received 4 December 2017; editorial decision 9 February 2018; accepted 14 February 2018. scant hemoptysis. He was enrolled in an institutional review Correspondence: J.  H. Powers  III, MD, Clinical Research Directorate/Clinical Monitoring board–approved clinical research protocol, and informed con- Research Program, Leidos Biomedical Research, Inc., NCI Campus at Frederick, 5601 Fishers Lane, Room 4D50, Bethesda, MD 20892 (john.powers@nih.gov). sent was obtained and documented. On examination, his body Open Forum Infectious Diseases temperature was 38.2 C, blood pressure 126/91 mm Hg, heart © The Author(s) 2018. Published by Oxford University Press on behalf of Infectious Diseases rate 88 beats per minute, respiratory rate 18 breaths per min- Society of America. This is an Open Access article distributed under the terms of the Creative ute, and oxygen saturation 98% breathing ambient room air. He Commons Attribution-NonCommercial-NoDerivs licence (http://creativecommons.org/licenses/ by-nc-nd/4.0/), which permits non-commercial reproduction and distribution of the work, in any appeared thin and lethargic, but was not in acute distress, and medium, provided the original work is not altered or transformed in any way, and that the work was spitting blood-tinged saliva into a cup. He denied dyspnea is properly cited. For commercial re-use, please contact journals.permissions@oup.com DOI: 10.1093/ofid/ofy038 and was phonating normally. He was tender diffusely around Epiglottitis in the Immunocompromised • OFID • 1 Downloaded from https://academic.oup.com/ofid/article-abstract/5/3/ofy038/4868583 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Figure  1. Topogram and sagittal view of the neck on computerized tomography scan performed on the day of presentation showing classic “thumbprint” sign due to swelling of epiglottis. the neck. er Th e were no other abnormal examination findings. right tonsillar area isolated Enterobacter cloacae resistant to cefa- His laboratory findings showed a white cell count of 1430 per zolin, cefoxitin, ceftazidime, ceftriaxone, co-amoxiclav, ampi- cubic millimeter (absolute neutrophil count 0 per cubic mil- cillin, aztreonam, and piperacillin/tazobactam; subsequently, limeter), hemoglobin 10.7  g per deciliter, and platelets 33 000 he was prescribed meropenem (750  mg, every 8 hours). He per cubic millimeter. Radiographic imaging showed a classic clinically improved with this antibiotic regimen, and follow-up “thumbprint” sign at the site of the epiglottis (Figure 1). Direct laryngoscopy 17 days later showed significant improvement in laryngoscopy showed an erythematous, enlarged, and pos- the appearance of the epiglottis (Figure 3). teriorly ptotic epiglottis that was not necrotic (Figure  2). e Th patient immediately received intravenous piperacillin/tazo- DISCUSSION bactam (3.375 g, every 6 hours), vancomycin (400 mg, every 6 Epiglottitis is a medical emergency, with the potential serious hours), and micafungin (100 mg, once daily), as well as intrave- complication of airway compromise secondary to the inflam- nous dexamethasone (4 mg, every 6 hours) and nebulized race- matory response to infection in the upper airway. It is a clinical mic epinephrine (0.5 mL of 2.25%, every 6 hours). He clinically diagnosis characterized by odynophagia, stridor, drooling, and improved while being closely monitored in the intensive care a “hot potato” voice. The patient may also show signs of sep- unit; there was no need for definitive airway management by sis in cases of severe infection. Direct fibreoptic laryngoscopy intubation. Blood cultures showed no growth, but endoscop- shows an inflamed and swollen epiglottis; however, examination ically directed cultures from directly observed exudate on the should be done with caution as it can lead to rapid airway com- promise. Radiology, including lateral x-ray of the cervical spine or computerized tomography, may aid in diagnosis by showing a classic “thumbprint sign,” evidence of soft tissue swelling of the epiglottis. While antimicrobials are part of treatment, additional support, including steroids [3], is used to reduce the inflamma- tion, and intubation/tracheostomy under carefully monitored conditions maintains the collapsing airway. In cases where there is abscess formation, surgical debridement may also be neces- sary. Isolated necrosis of the epiglottis also can occur [29]. Demographics of Epiglottitis in the Immunocompromised We performed a literature search evaluating epiglottitis in the immunocompromised host, which yielded 48 published cases from 34 published reports (Table 1) [4–37 ]. Patient ages ranged from 4 months to 70 years, with a mean age of 35.5 years, with 23 male and 25 female patients. Twenty-four had immuno- compromise secondary to cancer and/or chemotherapy, and 12 patients were positive for HIV. The remainder had a variety of causes of immunocompromise, including Epstein-Barr virus Figure 2. Laryngoscopy image of epiglottis showing erythematous and enlarged epiglottis. (EBV) mononucleosis, renal transplantation, and drug-induced 2 • OFID • Chen et al Downloaded from https://academic.oup.com/ofid/article-abstract/5/3/ofy038/4868583 by Ed 'DeepDyve' Gillespie user on 16 March 2018 In our patient, there was no stridor or pus on laryngoscopy. Neutrophils are the key effector cells of the innate immune system, so when patients become neutropenic (<500 per cubic millimeter), they become susceptible to infections. Sore throat due to mucositis may be common in patients receiving chemo- therapy for malignancy, but there should be a high index of suspicion if symptoms worsen or progress to include difficulty swallowing, clearing secretions, or breathing. We postulate that there are 3 reasons why, despite the ongoing inflammation and medical intervention, this patient’s airway remained competent without any need for airway support. First is that, anatomic- ally, this 16-year-old’s head and neck anatomy may be different compared with younger children with Hib epiglottitis. There is more space for the swelling to expand before impinging on the airway. Second, there is an inverse correlation between patient age and risk of laryngospasm [38]. Third, the severity of his immunocompromise from aplastic anemia may have limited Figure 3. Follow-up laryngoscopy image showing significant improvement in ery- the extent of host response, thereby presenting a lower-than-ex- thema and swelling. pected degree of inflammation and swelling. Clinical Course, Treatment, and Outcomes of Epiglottitis in the neutropenia (see the footnote to Table 1). Of these 48 patients, Immunocompromised 18 were neutropenic, defined by an absolute neutrophil count The majority of cases were empirically treated initially with and/or total white cell count of less than 1000 per cubic millim- broad-spectrum antibiotics. Of the 21 patients in whom fun- eter. The range of underlying causes of immunocompromise in gal organisms were isolated, 7 empirically received antifungal neutropenic patients was similar to that in non-neutropenics. agents, including 2 patients with concomitant neutropenia. Clinical Presentation of Epiglottitis in the Immunocompromised As many of the organisms isolated are part of the normal oro- Epiglottitis has previously been reported in 1 other patient pharyngeal flora, especially Candida sp, their role in infection vs with aplastic anemia [12]. Our patient presented with typical colonization often is unclear. The benefits or harms of adminis- signs and symptoms of epiglottitis similar to those observed in tering antifungals empirically are unclear from this case series. immunocompetent patients. Specifically, in the reviewed case Prognosis of Epiglottitis in the Immunocompromised reports of immunocompromised patients, patients presented Of the 48 case reports, 13 people died and 35 survived (27% with symptoms of respiratory distress, stridor, fever, drooling, overall mortality), highlighting the life-threatening nature of sore throat, odynophagia, and dysphagia [4–37]. epiglottitis. Of the neutropenic patients, 6 died and 12 survived, giving a slightly higher mortality of 33% (Table  1). Two of 3 patients with tongue involvement were neutropenic. Table  1. Demographics of Epiglottitis in the Immunocompromised Table  2 shows the interventions used in addition to anti- According to 48 Cases from Published Studies [4–37] microbial agents and their associated mortalities in the patients Demographic Data for Cases who received them. Mean age (SD, range), y 35.5 (20.1, 4 mo–70 y) It is not possible to determine the effects of various interven- Sex Male 23 48% tions on mortality from this case series. Intubation and trache- Female 25 52% ostomy may be used in more severe cases, so higher mortality Underlying condition Malignancy 24 50% with these interventions may reflect higher baseline risk of HIV 12 25% death independent of the interventions administered. Other 12 25% Neutropenia ANC or WBC <1000 18 38% Organisms Isolated in Immunocompromised Patients Mortality Neutropenic 33% In 29 patients, a single organism was isolated from cultures of the Not neutropenic 23% throat, sputum, blood, or tissue biopsy (either from an isolated Abbreviations: ANC, absolute neutrophil count; WBC, total white blood cell count. site or from multiple sites), while 3 patients had either no growth Other causes of immunocompromise included Epstein-Barr virus (EBV) mononucleosis in pregnancy, bone marrow aplasia of unknown origin, hypocellular bone marrow of on cultures or they were not done. The remaining 16 patients unknown origin, aplastic anemia, virus-associated hemophagocytic syndrome secondary grew multiple organisms. A summary of organisms is shown in to EBV infection, renal transplantation, procainamide-induced neutropenia, infection-re- lated hemophagocytic lymphohistiocytosis, Cytomegalovirus-related pancytopenia, sys- Table  3. The most frequent organism isolated from either cul- temic lupus erythematosus, and drug-induced agranulocytosis. In 1 patient, the cause of immunocompromise was not documented. tures or biopsy was Candida spp, followed by Streptococcus spp. Epiglottitis in the Immunocompromised • OFID • 3 Downloaded from https://academic.oup.com/ofid/article-abstract/5/3/ofy038/4868583 by Ed 'DeepDyve' Gillespie user on 16 March 2018 Table 2. Supportive Treatments Used in Addition to Antimicrobial Therapy rod-shaped organism oen f ft ound in the normal flora of the in the 48 Published Cases of Epiglottitis in the Immunocompromised [4–37] gastrointestinal tract [39]. It is also a nosocomial pathogen, with previous documentations of E.  cloacae outbreaks [40]. Supportive Treatment No. Mortality, % Flynn et al. suggested that Enterobacter from patients’ endogen- Intubation 30 37 ous flora can be the source of “nosocomial” Enterobacter infec- Tracheostomy 10 40 tion [41]. Our patient did recently have a hospital admission Steroids 9 33 in Jamaica and receipt of prior antibiotics, so it is unclear Granulocyte stimulating factor 5 20 whether the source of his infection was nosocomial or com- Surgical debridement 2 0 Racemic epinephrine 2 0 munity acquired. Nonetheless, this finding has implications for the choice of empirical antimicrobial therapy for the initial management of epiglottitis in immunocompromised patients. Eight of the neutropenic patients grew Candida spp and were Gram-negative and fungal infections should be considered in subsequently treated with antifungal agents (11 of 31 non-neu- this setting. tropenic patients grew Candida spp). The organisms grown from neutropenic patients showed more variety and were less predict- CONCLUSIONS able, such as Prevotella spp and Serratia marcescens, compared In the immunocompromised patient, there should be a low with primarily Streptococcus pneumoniae and Candida albicans threshold of suspicion for diagnosing acute epiglottitis, particu- in non-neutropenic patients. In 2 patients, cultures were not larly in those who are neutropenic. The immunocompromised done, diagnosis was made on a clinical basis, and the infection state and neutropenia do not rule out diseases caused by neutro- resolved without intervention. There was 1 case where there was philic infiltration as tissue-based inflammation still may result in no growth from blood cultures, throat swabs, or tracheal aspir- disease. Epiglottitis in reported cases presents similarly in immu- ate, but the patient survived and the disease resolved after receipt nocompromised and immunocompetent patients. Early recog- of cefotaxime, erythromycin, and metronidazole. nition can allow prompt treatment, including administration of Here we report the first documented case of acute epiglot- broad-spectrum antimicrobials and perhaps antifungals, given titis associated with Enterobacter cloacae, a gram-negative the wide range of organisms isolated. The impact of broad-spec- trum antimicrobials with additional antifungals on outcome is unknown given that the organisms isolated also are part of the Table  3. Organisms Grown From 48 Cases of Epiglottitis in normal oropharyngeal flora, and whether they are colonizing or Immunocompromised Patients From Published Cases [4–37] causing infection often is unclear. Airway management is para- mount, but endotracheal intubation is not always necessary and Organism Isolated Neutropenic Total % of All Cases was not necessary in our patient. Sedation, inhalers, and racemic Candida spp 8 19 40 epinephrine should be avoided [3]. Rapid treatment with steroids Streptococcus spp 2 12 25 Staphylococcus spp 2 5 10 to reduce the immediate inflammation, along with antimicrobials Cytomegalovirus 2 5 10 to treat the underlying infection, has been associated with shorter Aspergillus spp 2 4 8 intensive care unit and overall length of hospital stay; close mon- Serratia spp 3 3 6 itoring and good nursing care are essential for the appropriate Enterococcus spp 2 2 4 management of epiglottitis in the immunocompromised patient. Corynebacterium diphtheriae 1 2 4 Escherichia coli 1 2 4 Acknowledgments Neisseria spp 1 2 4 Financial support. This project has been funded in whole or in part Prevotella spp 2 2 4 with federal funds from the National Cancer Institute, National Institutes of Pseudomonas spp 1 2 4 Health, under Contract No. HHSN261200800001E. 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