Refractory Pneumonia in a 12-year-old Girl with Hemoglobin SS Disease

Abstract

A 12-year-old girl with hemoglobin SS disease presents with fever, cough with sputum production, chest pain, right shoulder pain, bilateral leg pain and decreased appetite before the coronavirus disease 2019 pandemic. She had a 2-day admission 1 week earlier for acute chest syndrome, her second hospitalization in 12 months. She received intravenous (IV) ceftriaxone and azithromycin but no blood products and was discharged on 5 more days of amoxicillin and 3 more days of azithromycin after resolution of her symptoms of fever, cough, chest pain, right shoulder pain, and decreased appetite. She now reports that her symptoms have been persistent since this most recent discharge despite the antibiotic treatment. The cough has been worsening, and the bilateral leg pain is new compared with her symptoms during the most recent hospitalization. She denies vomiting, diarrhea, abdominal pain, rashes, headache, or vision changes. It is influenza season, but she has no known sick contacts and no exposures to zoonotic hosts, and she lives in an urban area in the northern Midwest.Vital signs include a temperature of 102.9°F (39.4°C), heart rate of 148 beats/min, blood pressure of 121/69 mm Hg, respiratory rate of 28 breaths/min, and oxygen saturation of 98% on room air. Physical examination shows an alert but uncomfortable-appearing girl with reproducible pain on palpation of her sternum, rib cage, and right shoulder. Her lung examination reveals diminished breath sounds over the right middle lobe but is otherwise clear to auscultation. Cardiac and abdominal examination findings are normal. There is no scleral icterus or jaundice. A normal saline bolus is given, as is morphine and ketorolac for pain control. Her chest radiograph shows worsening consolidation of the medial basal segment of the right lower lobe (Fig 1) compared with the imaging during her previous hospitalization. Initial laboratory data show the following: white blood cell count, 22,200/µL (22.2 × 109/L) (reference range, 4,000–15,300/µL [4.0–15.3 × 109/L]), which is elevated compared with her baseline and most recent hospitalization values; hemoglobin level, 10.9 g/dL (109 g/L) (reference range, 12.0–15.0 g/dL [120–150 g/L]) but within her baseline range of 10 to 12 g/dL (100-120 g/L) and unchanged from previous hospitalization values; reticulocyte percentage, 4.2% (reference range, 0.5%–2.2%); and platelet count, 429 × 103/µL (429 × 109/L) (reference range, 150–450 × 103/µL [150–450 × 109/L]). A blood culture sample is collected. Empirical ceftriaxone and azithromycin are started, and the patient is admitted to the hospital acute care floor for further management.Despite 3 days of empirical antibiotic treatment, daily fevers persist. Repeated and additional laboratory tests show a white blood cell count of 35,160/µL (35.16 × 109/L), with 82.7% neutrophils (reference range, 36%–72%); a platelet count of 1,889 × 103/µL (1,889 × 109/L); an erythrocyte sedimentation rate of 125 mm/hr (reference range, 0–10 mm/hr); a C-reactive protein level of 25.5 mg/dL (255 mg/L) (reference range, 0–1 mg/dL [0–10 mg/L]); a procalcitonin level of 52 ng/dL (0.52 μg/L) (reference range, <11 ng/dL [<0.11 μg/L]); a uric acid level of 1.6 mg/dL (0.10 mmol/L) (reference range, 2.0–6.3 mg/dL [0.12–0.37 mmol/L]); a lactate dehydrogenase level of 425 U/L (7.10 µkat/L) (reference range, 370–840 U/L [6.18–14.03 µkat/L]); and an angiotensin-converting enzyme inhibitor level of 29.0 U/L (483.3 nkat/L) (reference range, 13–100 U/L [216.7–1,666.7 nkat/L]). Several blood culture samples have been collected and continue to be without growth. Additional testing, including Epstein-Barr virus and cytomegalovirus serologies and nucleic acid amplification testing for enteric pathogens, parvovirus B19, influenza A and B, adenovirus, parainfluenza, mycoplasma, and Chlamydia pneumoniae, are sent to the laboratory. Urine Blastomyces and Histoplasma antigens are also collected.A computed tomographic scan of the chest with contrast shows a masslike consolidation in the right lower lobe, scattered bilateral pulmonary nodules, subcarinal and right hilar lymphadenopathy, and a small right pleural effusion (Fig 2). A magnetic resonance image of the shoulder shows no evidence of osteomyelitis, but multiple slightly enlarged lymph nodes are incidentally noted in the right axillary and lower cervical chain region. Antibiotic therapy is empirically broadened to cefepime and linezolid; however, the patient continues to have daily fevers.A bronchoscopy with a bronchoalveolar lavage (BAL) reveals a mucus plug in a subsegmental bronchus branching from the right lower lobe bronchus. BAL fluid is sent for analysis, Gram-stain, and aerobic, anaerobic, mycobacterial, fungal, and viral cultures.Acute chest syndrome can be caused by pulmonary infarction, fat embolism, or, most commonly, viral or bacterial pathogens. The most common bacterial pathogens are Streptococcus pneumoniae, Staphylococcus aureus, and atypical pathogens such as Chlamydia and Mycoplasma. Viral pneumonia was initially considered, but the pattern of focal consolidation on chest radiograph in combination with persistent fevers, elevated inflammatory markers, and negative viral studies made this diagnosis less likely. This patient was treated for community-acquired pneumonia, but she continued to worsen. The differential diagnosis was broadened to include less common pathogens such as fungi, postobstructive pneumonia due to congenital airway malformation, extraluminal airway compression, neoplasm, and pulmonary sarcoidosis. Bronchoscopy was performed to evaluate for an airway malformation or obstruction and to try to isolate an infectious organism. Sarcoidosis was considered, but her young age, acute onset, chest radiography pattern, lack of extrapulmonary disease, and normal angiotensin-converting enzyme inhibitor level made this etiology less likely.BAL direct examination shows broad-based budding yeasts, and culture speciates into Blastomyces dermatitidis, revealing the diagnosis. Urine antigens for Blastomyces and Histoplasma are positive. Viral and atypical bacterial testing results are negative. The patient is started on amphotericin, and oral itraconazole and antibacterials are discontinued. A full-body and brain magnetic resonance image reveals no extrapulmonary fungal infection. Inflammatory markers and thrombocytosis decrease after initiation of antifungal treatment.B dermatitidis and Blastomyces gilchristii are 2 species of dimorphic fungi endemic to North America, predominantly in the Great Lakes region, the Mississippi and Ohio river valleys, and the St Lawrence River areas. They are dimorphic fungi and thrive in forested, acidic, sandy soils near water containing decaying vegetation or organic matter. When spores of either species are inhaled, they can give rise to a systemic pyogranulomatous infection called blastomycosis. Acute pulmonary blastomycosis is 1 manifestation of the infection. Incubation time after environmental exposure to the spores is generally 3 to 6 weeks. Presenting symptoms can include any combination of the following: cough, fever, shortness of breath, weight loss, night sweats, chills, hemoptysis, and pleuritic chest pain. (1) Acute pulmonary blastomycosis is frequently indistinguishable from bacterial or viral pneumonia by history and physical examination findings. (2) Blastomycosis can also cause a chronic pneumonia presenting as low-grade fevers, productive cough, hemoptysis, chest pain, and weight loss. Pulmonary blastomycosis can progress to disseminated blastomycosis, affecting the skin as verrucous lesions or nodules; the musculoskeletal system as osteomyelitis or arthritis; the genitourinary system as prostatitis, epididymo-orchitis, or tubo-ovarian abscess; or the central nervous system (CNS) as meningitis, epidural, or intracranial abscesses. However, some patients may develop the aforementioned extrapulmonary manifestations without preceding symptomatic Blastomyces pneumonia. (3)Chest radiographs in pulmonary blastomycosis most often show alveolar infiltrates. These are more often unilateral and in the lower lobes but can also involve multiple lobes, including upper lobes. Chest radiographs can also show a reticulonodular patterns or can be without airspace consolidation. (4) Computed tomographic scans can show nodules, consolidations without cavitation, or tree-in-bud opacities (areas of centrilobular nodules with a linear branching pattern that can be seen in bacterial or fungal pneumonia, cystic fibrosis, bronchiolitis, and neoplasms). (5)Definitive diagnosis is established by growth of organism from culture or by visualization of organism on tissue histologic analysis. Colonization with blastomycosis has not been reported in the literature. Cultures of the mold on Sabouraud dextrose agar grow in 1 to 4 weeks, with BAL samples yielding a positive culture in approximately 92% of patients. Cytologic examination of sputum, pleural fluid, or BAL fluid has low diagnostic yield but is available in shorter time courses than culture. If present, Blastomyces cells are easily differentiated from other fungal cells based on size and characteristic morphology of the broad-based budding yeast. (6) Serologic testing can be useful but often cross-reacts with other mycoses, especially Histoplasma. Likewise, antigen testing cross-reacts with other mycoses, but sensitivity of urine antigen testing for mycoses is good. (1) Antigen levels can also be useful in monitoring disease course, as levels decline with successful treatment and increase with disease recurrence. (7) A thorough history and physical examination should be conducted with possible extrapulmonary manifestations in mind. Further targeted or whole-body imaging may be needed depending on the presentation.The choice and duration of treatment of blastomycosis depends on several factors, including clinical form, severity of disease, and immune status. In severe or disseminated disease, including extrapulmonary or progressive pulmonary disease and in patients who are immunocompromised, a lipid formulation of amphotericin B or amphotericin B deoxycholate (conventional amphotericin formulations) should be initiated. (8) Amphotericin B deoxycholate is associated with higher toxicity risk compared with the lipid formulation. The adverse effects associated with amphotericin B include nephrotoxicity, fever, rigors, nausea, and vomiting. In CNS infection, the lipid formulation of amphotericin B is preferred because of fewer adverse effects and possibly improved CNS penetration. (7) Therapy can transition to oral agents (itraconazole or voriconazole) once there is improvement in symptoms (fever, cough, night sweats, muscle pain, chest pain, and fatigue), which is usually seen after 1 to 2 weeks from initiation of IV treatment for mild or moderate disease and after 4 to 6 weeks for CNS or severe disease.The Infectious Diseases Society of America has published clinical practice guidelines for the management of blastomycosis, with therapeutic strategy partially based on disease severity (mild, moderate, or severe) but without clearly defining each severity level. Consultation with an infectious disease physician or other provider with experience in the management of blastomycosis is recommended. Oral therapy in mild or moderate disease is most commonly itraconazole, although voriconazole has been a successful alternative treatment for Blastomyces CNS disease, refractory blastomycosis, and immunosuppressed patients. (8) Both posaconazole and isavuconazole have also been proved effective and are becoming more popular alternative treatments. Additional alternative treatments for mild to moderate disease can consist of fluconazole or ketoconazole; however, these are less effective compared with itraconazole. Duration of oral therapy should generally be 6 to 12 months after 1 to 2 weeks of IV therapy in mild or moderate disease, at least 12 months for osteoarticular infections, and at least 12 months after 4 to 6 weeks of IV therapy in severe or CNS disease.Amphotericin is discontinued on day 10 of antifungal treatment (hospital day 18) once the patient is afebrile for 48 hours, her oral itraconazole serum level is therapeutic, and she has improvement in all her presenting symptoms. She is discharged from the hospital on day 22 of her current hospitalization and continues single therapy with oral itraconazole for 12 months with good adherence. Chest radiography findings returned to baseline by 3 months of treatment.Blastomycosis or other endemic fungus must be considered on the differential diagnosis in patients with suspected pneumonia not responding to conventional treatment, especially in those who live or have recently traveled in endemic areas.Acute pulmonary blastomycosis presents variably with cough, fever, shortness of breath, chest pain, and/or productive cough and may also include weight loss, hemoptysis, and night sweats as presenting symptoms.Diagnosis is made by culture of bronchoalveolar lavage washings, sputum, or pleural fluid or by histologic analysis of tissue specimens. Serum and urine antigens are noninvasive tests to help guide further diagnostic testing or otherwise support a clinical diagnosis.Patients diagnosed as having pulmonary blastomycosis must be evaluated for extrapulmonary disease to determine treatment agent and duration.