As a result of universal childhood immunization programs that include vaccination against Haemophilus influenzae type B, epiglottitis, a potentially life threatening infection, is now uncommon.1 Necrotizing epiglottitis (NE), a rare variant of this condition, is even less common with only 5 reported cases in the literature to date.2–6 We describe the case of a male infant presenting with respiratory compromise secondary to NE, who was subsequently found to be infected with human immunodeficiency virus (HIV).
A previously thriving 4-month-old Caucasian infant presented with a 7-day history of fever, cough, reduced oral intake, loose stools, and lethargy. Four days prior, he had been seen in the emergency department and discharged with a presumptive diagnosis of mild bronchiolitis. His perinatal, past medical, and family history were otherwise unremarkable. His immunizations were up to date; he had received 2 sets of routine vaccinations including H. influenzae type B and the 7-valent pneumococcal conjugate vaccines.
On examination he was lethargic and looked unwell. His weight was 6.75 kg (25th–50th centile), temperature 39.2°C, heart rate 195 per minute, respiratory rate 68 per minute, and oxygen saturation 93% in room air. He had marked subcostal recession with mild to moderate tracheal tug. Auscultation revealed coarse crepitations and wheezing over both lung fields. There was no drooling, stridor, hepatosplenomegaly, or lymphadenopathy. Oxygen saturation improved to 100% with 1 L/min oxygen via nasal prongs.
Initial investigations revealed hemoglobin 11.0 g/dL, white blood cell count 2.7 × 109/L (absolute neutrophil count 0.08 × 109/L, lymphocyte count 1.97 × 109/L), and platelet count 241 × 109/L. C-reactive protein was 209 mg/L (normal <8 mg/L). Liver function tests were normal. A chest radiograph showed mild hyperinflation with perihilar hazy opacities bilaterally with a discrete, confluent opacity in the right upper lobe suggestive of consolidation. He was started on intravenous flucloxacillin and cefotaxime for suspected bacterial pneumonia and/or sepsis.
Blood and urine cultures were negative. Cerebrospinal fluid microscopy and culture were negative. Direct immunofluorescence of a nasopharyngeal aspirate was negative for parainfluenza virus (1, 2, and 3), influenza virus (A and B), respiratory syncytial virus, adenovirus, and cytomegalovirus (CMV). However, CMV was subsequently isolated on culture from the nasopharyngeal aspirate and urine. Stool samples were culture negative for all viruses.
After a 10-day period of initial clinical improvement, his condition deteriorated suddenly with increased work of breathing and intermittent apnoeas, requiring a period of mechanical ventilation in the intensive care unit. During intubation, direct laryngoscopy revealed an ulcer on the right tonsil and a large necrotic defect on the superior aspect of the epiglottis. Formal endocopic laryngoscopy demonstrated more extensive pathology. Beside the erosion of the epiglottis, multiple ulcerations of the oropharynx and supraglottis were noted (a color video of the endoscopic examination is available for viewing at http://video.wch.org.au/genmed/necrotising_epiglottitis/). Swabs and biopsies were obtained from the affected areas for culture (bacterial and viral) and histology. A bronchoalveolar lavage (BAL) was performed. Antibiotics were changed to timentin and gentamicin.
Histology of the biopsy samples showed focal areas of ulceration with large numbers of Gram-positive and Gram-negative cocci. The adjacent tissue contained large numbers of lymphoid cells and histiocytes with few neutrophils. No viral inclusion bodies were seen. Staphyloccus aureus and CMV were later cultured from the tissue samples.
Streptococcus pneumoniae and S. aureus were cultured from the BAL-fluid. Polymerase chain reaction for Pneumocystis jiroveci on the BAL-fluid was negative. CMV serology (IgM and IgG) and CMV antigenemia were negative, but CMV was detected in the blood by polymerase chain reaction and was cultured from the BAL-fluid. Fundoscopy showed no evidence of CMV retinitis. Although treatment with ganciclovir was considered, his clinical condition improved significantly in the absence of any specific treatment for CMV and he was successfully extubated 2 days later. A subsequent video fluoroscopy revealed evidence of significant aspiration and nasogastric feeding was continued.
The unusual nature of the clinical course together with persistent neutropenia and lymphopenia, and the presence of CMV prompted further investigations. Immunoglobulins were normal apart from a raised IgA level of 3.19 g/L (normal range, 0.09–0.54). A neutrophil antibody screen was negative. Lymphocyte subset analysis revealed a low absolute CD4 count of 990 cells × 103/mm3 (47%) and a CD8 count of 480 cells × 103/mm3 (23%). The lymphocyte phytohaemagglutinin stimulation response was normal. A bone marrow aspirate showed reduced erythroblasts and a moderately increased, left-shifted myelopoiesis. An HIV antibody test was positive by enzyme-linked immunosorbent assay, which was confirmed by Western blot. The HIV viral load was greater than 100,000 copies/mL. His mother subsequently tested positive for HIV antibodies suggesting perinatally-acquired HIV infection. Genotypic testing demonstrated infection with wild-type virus (HIV-1 subtype C) in both. HIV testing had not been performed in pregnancy.
After parental counseling, highly active antiretroviral therapy was commenced with zidovudine, lamivudine, and nevirapine in combination with trimethoprim-sulfamethoxazole prophylaxis. Although recovery was slow he was discharged well 3 weeks later. The neutropenia had resolved by then. A repeat video flouroscopy showed mild aspiration with non-thickened fluids only. Six months after starting highly active antiretroviral therapy, he had an undetectable HIV viral load, was thriving, and had achieved normal developmental milestones.
To our knowledge this is the first report of NE in the context of HIV infection. NE is an extremely rare entity with only 5 cases previously reported in the English language literature.2–6 All previous cases have occurred in adults, the youngest patient being 17 years old.2
The typical clinical features of NE include pyrexia, sore throat, odynophagia, dysphagia, and respiratory distress. Progression can be rapid and fatal and all but one of the previously described cases required a period of mechanical ventilation for respiratory distress. Four of the 5 reported cases survived; 1 patient died of invasive aspergillosis and coexisting Gram-negative sepsis with Klebsiella pneumoniae.3 Morbidity is also high with ongoing dysphagia and recurrent aspiration events described in survivors, the latter presumably due to incomplete occlusion of the upper airway during swallowing.2,4 The sudden deterioration in our patient was probably related to an aspiration event, the occurrence of which was subsequently demonstrated on video fluoroscopy.
Immunocompromise appears to play an important role in the pathogenesis of NE. Of the 5 described cases, 3 had profound neutropenia at presentation.3,4,6 Coinfection with either CMV or EBV was described in 2 cases.2,6 Both viruses are known to modulate the host's immune defense significantly, facilitating immune evasion and rendering the host prone to secondary infections.7 Both mechanisms may have played a role in the pathogenesis of NE in our patient, who was profoundly neutropenic and lymphopenic at presentation.
The causative organism of NE is unclear. A wide variety of organisms have been isolated from biopsy samples of necrotic epiglottic tissue in previous cases including K. pneumoniae, Escherichia coli, Stenotrophomonas maltophilia, viridans streptococci, Staphyloccocus epidermidis, Bacteroides species, Neisseria species, Candida albicans, and Aspergillus flavus. However, many of these are commensal organisms, and therefore implicating them in the pathogenesis of NE is problematic. Nevertheless, it is possible that NE can result from an infection caused by normal pharyngeal flora in a vulnerable host.
CMV is one of the most common opportunistic infections in HIV-infected individuals.8 Gastrointestinal ulcerative disease and necrotic lesions secondary to CMV infection are well described in HIV-positive patients.9 CMV-related ulcers can be solitary or multiple and may occur in any part of digestive system. In contrast, ulcerative lesions in the respiratory tract caused by CMV infection are far less common.10,11 Notably, French et al10 described the case of a 43-year-old man with HIV-infection, who developed an ulcer in the vallecula with involvement of the ventral epiglottis, a biopsy of which revealed CMV inclusion bodies.
It is difficult to be certain whether the NE in our patient was caused by CMV infection. CMV was detected in blood, BAL fluid, and tissue cultures. However, no typical inclusion bodies were identified in the epiglottic tissue biopsy. Moreover, the patient's condition improved significantly without CMV-specific therapy. This, combined with the fact that the patient did not have other features suggestive of disseminated CMV such as thrombocytopenia or hepatosplenomegaly, contributed to the decision to withhold ganciclovir treatment. An alternative possibility is that CMV caused disruption of the mucosal integrity, which facilitated secondary bacterial invasion, a well described phenomenon in a variety of viral infections.12,13 Both S. aureus and S. pneumoniae have the potential to cause invasive disease and tissue necrosis.14 It is probable that these bacteria spread more rapidly and caused extensive tissue destruction in the context of coexisting neutropenia.
This case highlights the importance of considering underlying congenital or acquired immunodeficiencies, and specifically HIV-infection, in any patient presenting with an unusual form of epiglottitis or significant ulceration in the upper respiratory tract.
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