Rees 'Chip' Lee

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Scholarly Contributions

Chapters

• Lee, R. L., & White, C. W. (2008). Bronchiolitis Obliterans. In Pediatric Respiratory Medicine. doi:10.1016/b978-032304048-8.50077-3
• Lee, R. L. (2007). Nonobstructive Sleep Patterns in Children. In Clinician's Guide to Pediatric Sleep Disorder. CRC Press. doi:10.3109/9781420020991-3

Journals/Publications

• Ammar, L., Bird, K., Nian, H., Maxwell-Horn, A., Lee, R., Ding, T., Riddell, C., Gebretsadik, T., Snyder, B., Hartert, T., & Wu, P. (2024). Development and Validation of a Diagnostic Algorithm for Down Syndrome Using Birth Certificate and International Classification of Diseases Codes. Children (Basel, Switzerland), 11(10).
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  We aimed to develop an algorithm that accurately identifies children with Down syndrome (DS) using administrative data.
• Ammar, L., Riddell, C., Ding, T., Lee, R. L., Maxwell-Horn, A., Snyder, B. M., Gebretsadik, T., Hartert, T., & Wu, P. (2023). 39 Prenatal antibiotic exposure and risk of childhood asthma among children with Down syndrome. J Clin Transl Sci, 7(Suppl 1), 10. doi:10.1017/cts.2023.132
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  OBJECTIVES/GOALS: Children with Down syndrome are at increased risk of respiratory diseases including asthma. Prenatal antibiotic exposure has been shown to be associated with the development of childhood asthma. We aim to estimate the association between prenatal antibiotic exposure and childhood asthma among children with Down syndrome. METHODS/STUDY POPULATION: We conducted a retrospective cohort study of mother-child dyads of children with Down syndrome who were born 1995-2013. Both children and mothers were continuously enrolled in the Tennessee Medicaid Program (TennCare). Prenatal antibiotic exposure was measured using mother’s prescription fill records. Childhood asthma was defined between age 4.5-6 years by asthma-related healthcare encounters and asthma-specific medication fills. We assessed the association between prenatal antibiotic exposure and childhood asthma among children with Down syndrome using modified Poisson regression adjusting for maternal age, race, residence, education, marital status, smoking during pregnancy, maternal asthma status, delivery method, number of siblings, and children’s sex. RESULTS/ANTICIPATED RESULTS: Among 346 mother-child dyads of children with Down syndrome, 273 (78.9%) children were exposed prenatally to antibiotics and 104 (30.0%) had asthma by age 4.5-6 years. Among those who were exposed to at least one course, the median antibiotic course equaled 2 (interquartile range: 1-4). Prenatal antibiotic exposure was associated with a 20% increase in risk of childhood asthma in the unadjusted analysis (risk ratio [RR] 1.20, 95% confidence interval [CI] 0.78, 1.83) and a 26% increase in risk after adjustment (adjusted RR 1.26, 95% CI 0.79, 2.01). DISCUSSION/SIGNIFICANCE: In our study population, the majority of children with Down syndrome were exposed to antibiotics prenatally and the prevalence of asthma was high. Prenatal antibiotic exposure was associated with an increased risk of childhood asthma among children with Down syndrome; however, this increase was not statistically significant.
• Snyder, B. M., Patterson, M. F., Gebretsadik, T., Wu, P., Ding, T., Lee, R. L., Edwards, K. M., Somerville, L. A., Braciale, T. J., Ortiz, J. R., & Hartert, T. V. (2022). Validation of International Classification of Diseases criteria to identify severe influenza hospitalizations. Influenza and other respiratory viruses, 16(3), 371-375.
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  In this cohort study of hospitalized patients with linked medical record data, we developed International Classification of Diseases (ICD) criteria that accurately identified laboratory-confirmed, severe influenza hospitalizations (positive predictive value [PPV] 80%, 95% confidence interval [CI] 71-87%), which we validated through medical record documentation. These criteria identify patients with clinically important influenza illness outcomes to inform evaluation of preventive and therapeutic interventions and public health policy recommendations.
• Pugh, S., Heaton, M. J., Hartman, B., Berrett, C., Sloan, C., Evans, A. M., Gebretsadik, T., Wu, P., Hartert, T. V., & Lee, R. L. (2019). Estimating seasonal onsets and peaks of bronchiolitis with spatially and temporally uncertain data. Statistics in medicine, 38(11), 1991-2001.
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  RSV bronchiolitis (an acute lower respiratory tract viral infection in infants) is the most common cause of infant hospitalizations in the United States (US). The only preventive intervention currently available is monthly injections of immunoprophylaxis. However, this treatment is expensive and needs to be administered simultaneously with seasonal bronchiolitis cycles in order to be effective. To increase our understanding of bronchiolitis timing, this research focuses on identifying seasonal bronchiolitis cycles (start times, peaks, and declinations) throughout the continental US using data on infant bronchiolitis cases from the US Military Health System Data Repository. Because this data involved highly personal information, the bronchiolitis dates in the dataset were "jittered" in the sense that the recorded dates were randomized within a time window of the true date. Hence, we develop a statistical change point model that estimates spatially varying seasonal bronchiolitis cycles while accounting for the purposefully introduced jittering in the data. Additionally, by including temperature and humidity data as regressors, we identify a relationship between bronchiolitis seasonality and climate. We found that, in general, bronchiolitis seasons begin earlier and are longer in the southeastern states compared to the western states with peak times lasting approximately 1 month nationwide.
• Shykoff, B. E., & Lee, R. L. (2019). Risks from Breathing Elevated Oxygen. Aerospace medicine and human performance, 90(12), 1041-1049.
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  Effects of breathing gas with elevated oxygen partial pressure (Po₂) and/or elevated inspired oxygen fraction (Fo₂) at sea level or higher is discussed. High Fo₂ is associated with absorption problems in the lungs, middle ear, and paranasal sinuses, particularly if Fo₂ > 80% and small airways, Eustachian tubes, or sinus passages are blocked. Absorption becomes faster as cabin altitude increases. Pulmonary oxygen toxicity and direct oxidative injuries, related to elevated Po₂, are improbable in flight; no pulmonary oxygen toxicity has been found when Po₂ < 55 kPa [418 Torr; 100% O₂ higher than 15,000 ft (4570 m)]. Symptoms with Po₂ of 75 kPa [520 Torr; 100% O₂ at 10,000 ft (3050 m)] were reported after 24 h and the earliest signs at Po₂ of 100 kPa (760 Torr, 100% O₂ at sea level) occurred after 6 h. However, treatment for decompression sickness entails a risk of pulmonary oxygen toxicity. Elevated Po₂ also constricts blood vessels, changes blood pressure control, and reduces the response to low blood sugar. With healthy lungs, gas transport and oxygen delivery are not improved by increasing Po₂. Near zero humidity of the breathing gas in which oxygen is delivered may predispose susceptible individuals to bronchoconstriction.
• Shykoff, B. E., & Lee, R. L. (2018). Physiology of Oxygen Breathing in Pilots: A Brief Review. Aerospace Medicine and Human Performance, 90(12), 1041-1049.
• Stone, C. A., Gebretsadik, T., Lee, R. L., Evans, A., Hartert, T. V., Mitchel, E. F., Morrow, J., Wu, A. C., Iribarren, C., Butler, M. G., Larkin, E. K., Turi, K. N., & Wu, P. (2018). Trends in health care utilization for asthma exacerbations among diverse populations with asthma in the United States. J Allerg Clin Immunol Pract, 30601-3.. doi:10.1016/j.jaip.2017.07.038
• Stone, C., Gebretsadik, T., Lee, R. L., Evans, A. M., Hartert, T. V., Mitchel, E., Morrow, J., Wu, A. C., Iribarren, C., Butler, M. G., Larkin, E. K., Turi, K. N., & Wu, P. (2022). Trends in health care utilization for asthma exacerbations among diverse populations with asthma in the United States. The journal of allergy and clinical immunology. In practice, 6(1), 295-297.e5.
• Turi, K. N., Gebretsadik, T., Lee, R. L., Hartert, T. V., Evans, A. M., Stone, C., Sicignano, N. M., Wu, A. C., Iribarren, C., Butler, M. G., Mitchel, E., Morrow, J., Larkin, E. K., & Wu, P. (2018). Seasonal patterns of Asthma medication fills among diverse populations of the United States. The Journal of asthma : official journal of the Association for the Care of Asthma, 55(7), 764-770.
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  Nonadherence to controller and overuse of reliever asthma medications are associated with exacerbations. We aimed to determine patterns of seasonal asthma medication use and to identify time period(s) during which interventions to improve medication adherence could reduce asthma morbidity.
• Lee, R. L., Brown, R. F., Gebretsadik, T., Hartert, T. V., Dupont, W. D., & Wu, P. (2017). Alternative Viewpoint: Efficacy and Effectiveness of Respiratory Syncytial Virus Immunoprophylaxis in Children with Cystic Fibrosis - An Unsolved Question with More to Be Asked. Pharmacotherapy, 37(11), e120-e121.
• Sloan, C., Heaton, M., Kang, S., Berrett, C., Wu, P., Gebretsadik, T., Sicignano, N., Evans, A., Lee, R., & Hartert, T. (2017). The impact of temperature and relative humidity on spatiotemporal patterns of infant bronchiolitis epidemics in the contiguous United States. Health & place, 45, 46-54.
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  Infant bronchiolitis is primarily due to infection by respiratory syncytial virus (RSV), which is highly seasonal. The goal of the study is to understand how circulation of RSV is impacted by fluctuations in temperature and humidity in order to inform prevention efforts. Using data from the Military Health System (MHS) Data Repository (MDR), we calculated rates of infant bronchiolitis for the contiguous US from July 2004 to June 2013. Monthly temperature and relative humidity were extracted from the National Climate Data Center. Using a spatiotemporal generalized linear model for binomial data, we estimated bronchiolitis rates and the effects of temperature and relative humidity while allowing them to vary over location and time. Our results indicate a seasonal pattern that begins in the Southeast during November or December, then spreading in a Northwest direction. The relationships of temperature and humidity were spatially heterogeneous, and we find that climate can partially account for early onset or longer epidemic duration. Small changes in climate may be associated with larger fluctuations in epidemic duration.
• Turi, K. N., Gebretsadik, T., Lee, R. L., Hartert, T. V., Evans, A., Stone, C. A., Sicignano, N., Wu, A. C., Iribarren, C., Butler, M. G., Mitchel, E. F., Morrow, J., Larkin, E. K., & Wu, P. (2017). Seasonal patterns of Asthma medication fills among diverse populations of the United States. J Asthma, 7, 1-7. doi:10.1080/02770903.2017.1362426
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  Objective: Nonadherence to controller and overuse of reliever asthma medications are associated with exacerbations. We aimed to determine patterns of seasonal asthma medication use and to identify time period(s) during which interventions to improve medication adherence could reduce asthma morbidity. Methods: We conducted a retrospective cohort study of asthmatics 4–50 years of age and enrolled in three diverse health insurance plans. Seasonal patterns of medications were reported by monthly prescription fill rates per 1000 individuals with asthma from 1998 to 2013, and stratified by healthcare plan, sex, and age. Results: There was a distinct and consistent seasonal fill pattern for all asthma medications. The lowest fill rate was observed in the month of July. Fills increased in the autumn and remained high throughout the winter and spring. Compared with the month of May with high medication fills, July represented a relative decrease of fills ranging from 13% (rate ratio, RR: 0.87, 95% confidence interval, 95%CI: 0.72–1.04) for the combination of inhaled corticosteroids (ICS) + long acting beta agonists (LABA) to 45% (RR: 0.55, 95%CI: 0.49–0.61) for oral corticosteroids. Such a seasonal pattern was observed each year across the 16-year study period, among healthcare plans, sexes, and ages. LABA containing control medication (ICS+LABA and LABA) fill rates were more prevalent in older asthmatics, while leukotriene receptor antagonists were more prevalent in the younger population. Conclusions: A seasonal pattern of asthma medication fill rates likely represents a reactive response to a loss of disease control and increased symptoms. Adherence to and consistent use of asthma medications among individuals who use medications in reaction to seasonal exacerbations might be a key component in reducing the risk of asthma exacerbations.
• Armstrong, E. P., Malone, D. C., Yeh, W. S., Dahl, G. J., Lee, R. L., & Sicignano, N. (2016). The economic burden of spinal muscular atrophy. Journal of medical economics, 19(8), 822-6.
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  To evaluate the economic burden of spinal muscular atrophy (SMA).
• Smiley, M., Sicignano, N., Rush, T., Lee, R., & Allen, E. (2016). Outcomes of follow-up care after an emergency department visit among pediatric asthmatics in the military health system. The Journal of asthma : official journal of the Association for the Care of Asthma, 53(8), 816-24.
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  Asthma exacerbations frequently trigger emergency department (ED) visits. Guidelines recommend timely follow-up after an ED visit for asthma, however, other studies have questioned the quality of follow-up care and their effect on subsequent ED utilization. We evaluated follow-up care on asthma outcomes in pediatric asthmatics enrolled in the Military Health System (MHS) after an ED visit for asthma.
• Giri, N., Lee, R., Faro, A., Huddleston, C. B., White, F. V., Alter, B. P., & Savage, S. A. (2011). Lung transplantation for pulmonary fibrosis in dyskeratosis congenita: Case Report and systematic literature review. BMC blood disorders, 11, 3.
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  Dyskeratosis congenita (DC) is a progressive, multi-system, inherited disorder of telomere biology with high risks of morbidity and mortality from bone marrow failure, hematologic malignancy, solid tumors and pulmonary fibrosis. Hematopoietic stem cell transplantation (HSCT) can cure the bone marrow failure, but it does not eliminate the risks of other complications, for which life-long surveillance is required. Pulmonary fibrosis is a progressive and lethal complication of DC.
• Bhagtani, H., Love, E., Baci, G., Boughan, R. B., Krugman, S. D., Podraza, J., Lee, R. L., Nguyen, T. T., & Charles, E. (2007). Index of suspicion. Pediatrics in review, 28(6), 225-9.
• Bhagtani, H., Love, E., Baci, G., Boughan, R. B., Krugman, S., Podraza, J., & Lee, R. L. (2007). Index of Suspicion. Pediatrics in Review, 28(6), 225-229,. doi:10.1542/pir.28.6.225
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  A 6-year-old boy is admitted to the hospital because of right groin pain and refusal to bear weight. Yesterday, the child was seen in the ED because of pain in the right inguinal area, limp, and a history of rash along the right popliteal fossa that was not present at the time of his evaluation. Doppler ultrasonography of the testicles, radiographs of the hip, CBC, and ESR all yielded normal results. He was diagnosed as having hip strain and instructed to take ibuprofen and to return if his symptoms worsened or he developed a fever. He returns today, having a temperature of 102.6°F (39.3°C) and refusing to bear weight.On physical examination, the boy looks well but holds his right hip in an abducted, flexed, externally rotated position; refuses to move the leg; and complains of pain in the inguinal region. His temperature is 99.5°F (37.5°C), respiratory rate is 28 breaths/min, heart rate is 105 beats/min, and oxygen saturation on room air is 95%. Limb lengths and knee evaluation results are normal. There is no spinal tenderness, paraspinal muscle spasm, or lymphadenopathy. The other physical findings are normal.His WBC count is 13×103/mcL (13×109/L), Hgb is 11.9 g/dL (119 g/L), platelet count is 221×103/mcL (221×109/L), ESR is 33 mm/h, C-reactive protein (CRP) is 156 mg/L (normal, 0 to 3 mg/L), and creatinine phosphate kinase (CPK) concentration is 200 U/L (normal, 55 to 170 U/L). Findings on urinalysis are normal. An imaging test reveals the diagnosis.A 6-week-old boy is seen in the ED because of acute respiratory distress. He was well until this evening, when he started making a “funny noise” with each breath, was working hard to breathe, and felt warm.On arrival, the boy is in significant respiratory distress, with suprasternal and intercostal retractions and inspiratory stridor. The remainder of his examination findings are normal. A chest radiograph shows an obvious steeple sign. Viral croup is diagnosed. He is given intramuscular dexamethasone plus nebulized racemic epinephrine, and his symptoms resolve. The stridor returns 2 hours later, he is given a second epinephrine treatment, and his symptoms resolve. He is admitted to the hospital, has an uneventful 24-hour hospital stay with no additional respiratory distress, and is discharged.Four days later, he returns because of the same pattern of respiratory distress with inspiratory stridor. He had been well, but suddenly started working hard to breathe and making noise with each breath. He is admitted to the hospital and treated a second time with intramuscular dexamethasone and nebulized racemic epinephrine, and his symptoms resolve. Because of his age and the rapidity with which the stridor returned, the original diagnosis is questioned. A bedside diagnostic procedure is performed that reveals the diagnosis.A 3-year-old boy has had 1 week of worsening shortness of breath, wheezing, and fatigue. He had two coughing spells that produced sputum with streaks of blood. He has become a poor eater in the past few months, but does drink 2 L of whole milk daily, and he appears pale and tired. There has been no fever, vomiting, diarrhea, melena, or hematochezia, and no foreign body ingestion has been noted.On physical examination, the child appears thin and pale. He has tachypnea and tachycardia, but pulse oximetry readings are 100% on room air. Wheezes and coarse breath sounds are audible bilaterally. There is a 2/6 systolic ejection murmur heard best at the left sternal border, but no hepatosplenomegaly or clubbing. The rest of the physical findings are normal.His WBC count is 22.0×103/mcL (22.0×109/L) with 89 neutrophils, 9 lymphocytes, and no eosinophils; Hgb is 4.8 g/dL (48 g/L); and platelet count is 548×103/mcL (548×109/L). His mean cell volume is 61 fL, red cell distribution width is 26, and reticulocyte count is 7.3%. His serum iron concentration is 15 mcg/dL (2.7 mcmol/L), ferritin is 78 ng/mL (78 mcg/L), and total iron binding capacity is 497 mcg/dL (89 mcmol/L). Stool guaiac testing is positive, and gastric lavage produces blood clots. A coagulation profile is normal. Chest radiography shows bilateral patchy alveolar infiltrates with hilar lymphadenopathy. A chest CT scan shows widespread areas of airspace consolidation. Additional testing reveals the diagnosis.MRI showed a myositis of the right obturator externus and internus muscle and a small (1.0×1.5 cm) abscess in the obturator externus muscle. There was no evidence of osteomyelitis or significant hip joint effusion. Because the organism initially was unknown, broad-spectrum intravenous antibiotics were chosen, including vancomycin for methicillin-resistant Staphylococcus aureus (MRSA) and cefotaxime for gram-negative organisms.Both orthopedic and pediatric surgery were consulted. Pediatric surgery recommended CT evaluation to rule out retrocecal appendicitis or another pelvic disorder as causes of the myositis. The CT scan was negative for appendicitis, although it did show asymmetric enlargement of the right obturator externus muscle, with two hypodense regions measuring 2.6 cm at the mid portion and 1 cm at the distal area of the muscle. The right obturator internus muscle appeared to be thickened and edematous. No deep pelvic disease was seen. At that time, both surgeons felt that the area was too small and diffuse for percutaneous drainage and suggested continuation of intravenous antibiotics.The differential diagnosis of hip pain in this age group includes septic arthritis, osteomyelitis, toxic synovitis, pyomyositis, psoas abscess, juvenile idiopathic arthritis, fracture, tumor (Ewing sarcoma), Lyme arthritis, poststreptococcal or postviral reactive arthritis, Perthes disease, and slipped capital femoral epiphysis.In this patient, normal radiographs of the hips and negative Lyme and antistreptolysin titers narrowed the differential diagnosis considerably. Because of the high CRP, ESR, and CPK on admission, MRI was obtained to differentiate among the remaining pathologic conditions.Bacterial muscle abscesses occur most commonly in the large striated muscles, such as the quadriceps. In decreasing order of frequency, muscle areas that tend to be involved include thigh, buttock, arm, lower leg, groin, chest wall, flank, and shoulder. Such infections occur more commonly in tropical areas and are rare in temperate regions. Because pyomyositis occurs sporadically in the United States, it is easily misdiagnosed.Muscle abscesses occur in healthy children, with only 33% having a history of trauma or strenuous exercise. Infection can result from penetrating wounds with direct seeding, hematogenous spread of bacteria, or spread from an adjacent organ. The onset of symptoms generally is gradual, with patients experiencing muscle pain as long as several weeks prior to diagnosis. Fever is likely.Muscle abscess in children usually is caused by S aureus. Other potential pathogens include group A Streptococcus, Neisseria gonorrhoeae, and Enterococcus faecalis. A literature search reveals only 16 cases of obturator muscle abscess reported since 1966. These reports suggest that obturator muscle abscesses occur in an equal male-to-female ratio in children between the ages of 3 and 19 years. All patients previously were healthy and presented with the acute onset of hip, abdominal, or thigh pain; fever; and inability to bear weight on the affected leg. Patients tended to hold the leg in a position of flexion, abduction, and external rotation. Fifty percent of the reported children underwent arthrocentesis of the hip joint, which yielded negative results.Percutaneous drainage, sometimes with CT guidance, or open surgical drainage and broad-spectrum antibiotic treatment have proven to be successful treatments. CT-guided drainage can be important for microbiologic diagnosis as well as being an element of therapy. If there is one large abscess, CT-guided aspiration is particularly helpful as a therapy. If there are two or three abscesses, it is reasonable to drain at least the largest to obtain a microbiologic diagnosis. Open surgical drainage may be necessary if there is a complication such as contiguous osteomyelitis. None of the reported cases has had any significant, long-term sequelae.Antibiotics alone may be appropriate therapy in some cases, particularly those that are diagnosed early, or if there are small or multiple abscesses that cannot be drained.This patient experienced gradual symptomatic improvement during the first 48 hours of antibiotic therapy, with improved range of motion of the knee and hip. However, he remained febrile, warranting consideration of the need for a microbiologic diagnosis and alternative methods of therapy. The CT scans were re-evaluated and the abscesses drained percutaneously by interventional radiology under CT guidance on the boy's fourth hospital day. Fluid from the abscesses was cultured and a surgical drain placed, producing 22 mL of purulent fluid on his first postoperative day.Over the next 72 hours, the drainage decreased and became serous. On hospital day 6, cultures taken at surgery were growing S aureus susceptible to nafcillin, and the antibiotics were changed to nafcillin alone. The boy regained full range of motion with the help of physical therapy and was able to walk using a cane. By hospital day 7, the CRP had decreased from 156 mg/L to 2.0 mg/L, and repeat CT scanning of the pelvis revealed complete resolution of his abscesses. The surgical drain was removed. On the ninth hospital day, his CRP had decreased to 0.9 mg/L, and antibiotic therapy was changed to daily oral dicloxacillin. He was discharged with instructions to complete a total of 21 days of antibiotic therapy.Clinicians evaluating a child who has fever and hip pain and is unable to bear weight should consider obturator muscle or pelvic abscess in the differential diagnosis. MRI is the technique of choice for diagnosing these conditions and can differentiate pyomyositis from other conditions such as septic arthritis, osteomyelitis, and tumors. Management of muscle abscess usually includes percutaneous drainage, for both diagnostic and therapeutic reasons, and broad-spectrum intravenous antibiotics, including initial coverage for community-acquired MRSA pending culture results.A pediatric otolaryngologist performed fiberoptic laryngoscopy that showed a subglottic hemangioma occluding 75% of the airway. The boy was started on high-dose systemic corticosteroids and the following day was taken to the operating room for a more formal evaluation. No other airway lesions were noted on either rigid bronchoscopy or fiberoptic laryngoscopy. The hemangioma was treated with an intralesional steroid injection and a 4-week course of tapered systemic steroids.Stridor is a harsh, high-pitched respiratory sound that is caused by certain types of airway obstruction. Parents often describe stridor as a “wheeze,” and careful questioning by the pediatrician is required to differentiate the two. The differential diagnosis of stridor is extensive but can be narrowed quickly by using key components of the history and physical examination: age of the patient, acute versus chronic, febrile versus afebrile, and most important, the associated phase of the respiratory cycle.The phase in the respiratory cycle in which the stridor is heard correlates with the area of the obstruction. Inspiratory stridor suggests an extrathoracic cause, whereas expiratory stridor suggests an intrathoracic cause. Biphasic stridor suggests that both intra- and extrathoracic components of the trachea are involved or that the obstruction at any level of the airway has progressed to the point of being significant in both phases of respiration.The evaluation of stridor can include airway radiographs, esophagrams, laryngobronchoscopy, echocardiography, CT scan, and MRI. Identifying a specific portion of the airway on which to focus attention is important in determining how to pursue this diagnostic evaluation.In infancy, the three most common causes of inspiratory stridor are laryngomalacia, congenital subglottic stenosis, and vocal cord paralysis. However, many other conditions should be considered, including gastroesophageal reflux, acquired subglottic stenosis, laryngeal webs, diverticula, clefts, hemangiomas, papillomas, trauma, foreign bodies, and croup. Expiratory stridor can occur with asthma, tracheomalacia, trauma, or lesions in airway structures within the thoracic cavity. Biphasic stridor occurs with vascular rings and slings.Infants who have laryngomalacia usually present within the first 2 postnatal weeks. They have inspiratory stridor that often is exacerbated by agitation, can be absent at rest, and usually improves with prone positioning. Laryngomalacia frequently can be diagnosed based on history and examination alone, but a definitive diagnosis requires laryngoscopy.Infants who have congenital subglottic stenosis present shortly after birth or after their first upper respiratory tract infection. Airway radiographs often are suggestive but are not diagnostic and can appear normal, depending on the phase of respiration at the time the film was taken. Laryngoscopy and bronchoscopy are used for definitive diagnosis. The acquired form of subglottic stenosis frequently is seen in patients who have required prolonged intubation.Vocal cord paralysis most commonly is congenital but can follow trauma at the time of intubation. Affected infants have inspiratory stridor along with a weak cry. Congenital vocal cord paralysis can be associated with other CNS problems such as Arnold-Chiari malformations and hydrocephalus. Therefore, in addition to having laryngoscopy, these infants should receive a neurologic evaluation.This patient presented initially with the classic symptoms of viral croup: fever, respiratory distress, and inspiratory stridor. He had several days of runny nose and cough prior to the onset of respiratory distress. Clinicians should note that viral croup usually does not occur before 3 to 6 months of age, presumably due to the protective effects of pre-existing maternal antibody. The initial diagnosis of croup was considered correct because the child responded so well to standard treatment. When the boy presented for the second time with the same symptoms, however, a more formal evaluation was warranted.Hemangiomas occur in approximately 10% of infants, and most are cutaneous. They can be present in the head, neck, liver, intestines, and lung. Subglottic hemangiomas are rare, accounting for only 1.5% of all congenital anomalies of the larynx. Affected infants usually present within the first 2 to 6 postnatal months with a crouplike cough, inspiratory stridor, and respiratory distress. This symptomatology results from rapid growth of the hemangioma during a proliferative phase that can last up to 10 months, after which the hemangioma begins to involute.By 5 years of age, approximately 50% of subglottic hemangiomas have undergone complete involution, with the remainder taking as long as 12 years. The average age at diagnosis is 4 months, and the condition is seen more commonly in girls. Cutaneous hemangiomas are noted in 50% of cases and were not seen in this patient. Chest radiography can suggest the diagnosis, especially if there is an asymmetric steeple sign. Diagnosis does not require biopsy but is made by the characteristic appearance on laryngoscopy. (To view video endoscopy of hemangioma below the vocal cords, visit pedsinreview.org and click on Index of Suspicion, and then on Data Supplement 2.)Subglottic hemangiomas can be treated by conservative monitoring, systemic or intralesional steroids, carbon dioxide or potassium-titanyl-phosphate laser, tracheotomy, laryngotracheoplasty, interferon therapy, and administration of vincristine. Treatment is based on the severity of the symptoms, the size of the lesion, involvement of surrounding structures, and the abilities and experience of the otolaryngologist. The overall prognosis for subglottic hemangioma is good, but affected patients require monitoring and often multiple types of treatment. Although observation remains an option for some patients, mortality has been reported to be as high as 50% in untreated patients. (1)(2)Not all that wheezes is asthma, and not all stridor is croup. The history and physical examination are key in the assessment of stridor. The differential diagnosis is broad, and identifying the portion of the airway involved is critical in determining the appropriate diagnostic modality to pursue.Flexible bronchoscopy study with bronchoalveolar lavage revealed hemosiderin-laden macrophages. A subsequent open lung biopsy with histologic confirmation of hemosiderin-laden macrophages was necessary to confirm the diagnosis of pulmonary hemosiderosis. In addition, the biopsy showed interstitial fibrosis, suggesting more advanced disease. Multiple serologic studies were performed to search for an underlying cause, but results of all were negative. The boy was diagnosed as having idiopathic pulmonary hemosiderosis (IPH) and was treated with blood transfusions and high doses of corticosteroids.Pulmonary hemosiderosis is a condition in which the alveolar capillaries bleed. Repeated episodes of intra-alveolar bleeding cause accumulation of iron as hemosiderin in the pulmonary system and subsequent pulmonary fibrosis and iron deficiency anemia. Patients can present with either a sudden onset or more chronic course of hemoptysis, iron deficiency anemia, and pulmonary infiltrates.The exact cause of pulmonary hemosiderosis remains unknown, but three different types have been described. The first involves circulating antibodies to the basement membranes of lung tissue, as illustrated in Goodpasture syndrome. The second type has circulating immune complexes that cause vascular damage and disrupt the capillary endothelium and basement membrane in the lung, a pathologic state found in connective tissue disorders and Heiner syndrome, a hypersensitivity to cow milk. The last group is not associated with immune complexes or antibodies and includes bleeding disorders, cardiovascular disorders, and idiopathic pulmonary hemosiderosis. In children, idiopathic pulmonary hemosiderosis is the most common type.The presence of hemoptysis, iron deficiency anemia, and diffuse pulmonary infiltrates led to a high degree of suspicion for pulmonary hemosiderosis. Not all patients present with these findings, and only hemosiderin-laden macrophages found on bronchoalveolar lavage or lung biopsy are diagnostic of the disease. Finding the characteristic macrophages on lavage makes the diagnosis likely, and biopsy findings are definitive.Although idiopathic pulmonary hemosiderosis is the most common form of hemosiderosis to affect children, the diagnosis is one of exclusion. Many possible causes were considered in the case, but all were ruled out. The striking degree of microcytic anemia seen in this child is likely a combination of blood loss and iron deficiency related to his large intake of milk and is more profound than usually occurs in patients who have hemochromatosis.Heiner syndrome, which is related to milk protein hypersensitivity (but not volume of milk intake), was in the differential diagnosis, but the child had low casein and lactalbumin titers. His antiglomerular basement membrane antibodies were negative, ruling out Goodpasture syndrome. Other causes of hemosiderosis include cardiovascular abnormalities, systemic lupus erythematosus, Wegener granulomatosis, Henoch-Schönlein purpura, infections, neoplasms, drugs, toxins, and environmental molds such as Stachybotrys atra. Antinuclear antibody, anti-DNA antibodies, and antineutrophil cytoplasmic antibodies (abbreviated ANCA and present in Wegener granulomatosis and lupus) all were absent, and there was no evidence of bacterial or fungal infections. His parents denied any exposure to drugs, toxins, or molds, and a urinalysis and urine toxicology screen were negative.Treatment options are based on small case series or case reports. Systemic corticosteroids are used most commonly, especially in the acute phase of pulmonary hemorrhage. High doses of corticosteroids are used until pulmonary bleeding has ceased and the chest radiograph shows regression of the disease, which is usually within 1 to 2 months. Corticosteroids then are tapered and continued for about 2 years until the patient shows no signs of recurrent hemoptysis, an improvement in iron deficiency anemia, and a regression of opacifications on chest radiography.Other immunosuppressive agents have been used when corticosteroids have not evoked an adequate response. Agents such as azathioprine, hydroxychloroquine, cyclophosphamide, and methotrexate have been used with unclear results. Despite these therapies, the prognosis is relatively poor, with most patients progressing to pulmonary fibrosis and impaired pulmonary function within 2 to 3 years of onset of the disease. In the most extreme situation, lung transplantation may be indicated.Hemoptysis in children younger than 6 years of age is relatively uncommon unless there is substantial bleeding. Bleeding may come from the lower respiratory tract, but is more likely to originate in the upper respiratory tract, including the nasopharynx. Bleeding from the GI tract also can present as hemoptysis. Besides hemosiderosis, other lower respiratory causes of hemoptysis are respiratory infections, foreign body aspiration, and bronchiectasis. Idiopathic pulmonary hemosiderosis is a diagnosis of exclusion, and numerous other conditions must be ruled out before this diagnosis is made.
• Rancourt, R. C., Lee, R. L., O'Neill, H., Accurso, F. J., & White, C. W. (2007). Reduced thioredoxin increases proinflammatory cytokines and neutrophil influx in rat airways: modulation by airway mucus. Free radical biology & medicine, 42(9), 1441-53.
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  Thioredoxin (Trx) decreases viscosity of cystic fibrosis (CF) sputum. In this study reduced Trx increased the solubility and decreased the size of MUC5B glycoprotein while reducing disulfide bonds in sputum. Because Trx used as a mucolytic would enter airways, this study determined the effects of intratracheal instillation of reduced recombinant human thioredoxin (rhTrx) in naïve rat airways. Reduced rhTrx increased neutrophils and the cytokines TNFalpha, CINC2beta, and MIP3alpha in airways after 4 h. The effect of rhTrx was concentration-dependent. Exposure to saline, human serum albumin, or oxidized rhTrx at equal molarities did not increase airway neutrophils or cytokines. Instilling CF sputum (50 microl) into the lung before reduced rhTrx delivery attenuated these responses. This suggests that rhTrx reduces disulfide bonds present in CF sputum, limiting the reduction of other lung constituents. Together these findings indicate that the chemotactic and cytokine responses are due to the reducing potential of rhTrx and that the potential for inflammation in non-CF and CF patients given aerosolized rhTrx may differ. In parallel studies, increased amounts of the p65 subunit of NF-kappaB were present in nuclear extracts from rat lungs administered reduced rhTrx, suggesting a role for NF-kappaB in these proinflammatory responses.
• Lee, R. L., Rancourt, R. C., del Val, G., Pack, K., Pardee, C., Accurso, F. J., & White, C. W. (2005). Thioredoxin and dihydrolipoic acid inhibit elastase activity in cystic fibrosis sputum. American journal of physiology. Lung cellular and molecular physiology, 289(5), L875-82.
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  Excessive neutrophil elastase activity within airways of cystic fibrosis (CF) patients results in progressive lung damage. Disruption of disulfide bonds on elastase by reducing agents may modify its enzymatic activity. Three naturally occurring dithiol reducing systems were examined for their effects on elastase activity: 1) Escherichia coli thioredoxin (Trx) system, 2) recombinant human thioredoxin (rhTrx) system, and 3) dihydrolipoic acid (DHLA). The Trx systems consisted of Trx, Trx reductase, and NADPH. As shown by spectrophotometric assay of elastase activity, the two Trx systems and DHLA inhibited purified human neutrophil elastase as well as the elastolytic activity present in the soluble phase (sol) of CF sputum. Removal of any of the three Trx system constituents prevented inhibition. Compared with the monothiols N-acetylcysteine and reduced glutathione, the dithiols displayed greater elastase inhibition. To streamline Trx as an investigational tool, a stable reduced form of rhTrx was synthesized and used as a single component. Reduced rhTrx inhibited purified elastase and CF sputum sol elastase without NADPH or Trx reductase. Because Trx and DHLA have mucolytic effects, we investigated changes in elastase activity after mucolytic treatment. Unprocessed CF sputum was directly treated with reduced rhTrx, the Trx system, DHLA, or DNase. The Trx system and DHLA did not increase elastase activity, whereas reduced rhTrx treatment increased sol elastase activity by 60%. By contrast, the elastase activity after DNase treatment increased by 190%. The ability of Trx and DHLA to limit elastase activity combined with their mucolytic effects makes these compounds potential therapies for CF.
• Lee, R. L. (1998). Letters to the Editor. Military Medicine, 163(9), 624. doi:10.1093/milmed/163.7.iii
• Lee, R. L., Smith, E. R., Mas, M., & Davidson, J. M. (1990). Effects of intrathecal administration of 8-OH-DPAT on genital reflexes and mating behavior in male rats. Physiology and Behavior, 47, 665-669. doi:10.1016/0031-9384(90)90075-f
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  Systemic administration of the 5HT1A receptor agonist, 8-OH-DPAT, consistently decreases the threshold of ejaculatory behavior and enhances some aspects of arousal. Previous findings by others demonstrated the in copula ejaculatory behavior effect using intrathecal (IT) injection at the level of the lumbosacral spinal cord, but the dose used was in the range that produced results systemically. This study aimed at a) a more comprehensive study of the sexual effects of 8-OH-DPAT and b) use of IT doses of 8-OH-DPAT below those effective when administered systemically. The ex copula genital reflex test showed severe inhibition. At doses of 5 micrograms or more, significant inhibition of the percentage of rats displaying ejaculation occurred, and the two highest doses also significantly reduced the percentage of rats displaying erection. In the in copula mating test, 20 and 80 micrograms IT 8-OH-DPAT, significantly reduced ejaculation latency, intromission frequency and intercopulatory interval. Copulatory plugs, collected at the highest dose only, showed a trend towards weight reduction. We conclude that the facilitation of ejaculatory behavior and some measure of arousal by 8-OH-DPAT can be mediated directly via the lumbosacral spinal cord. An hypothesis for explaining the inhibitory effect on ejaculation ex copula is presented, but the inhibitory effect on erectile reflexes is without interpretation.
• Schnur, S. L., Smith, E. R., Lee, R. L., Mas, M., & Davidson, J. M. (1989). A component analysis of the effects of DPAT on male rat sexual behavior. Physiology and Behavior, 45, 897-901. doi:10.1016/0031-9384(89)90212-6
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  Male rat sexual behavior was examined in a variety of tests following a single acute IP injection of the serotonin1A (5-HT1A) receptor agonist 8-hydroxy-2-(di-n-propylamino)tetralin (DPAT). The objective was to determine the effects of 5-HT1A receptor stimulation on the components of sexual behavior (arousal/motivation, erection and ejaculation) using this prototypical 5-HT1A ligand. In the ex copula genital reflex test, DPAT dramatically inhibited ejaculation and the display of penile erections. When examined in the mating behavior test, DPAT caused a significant reduction in intromission frequency (IF), ejaculation latency (EL), intercopulatory intervals (ICI) and postejaculatory interval (PEI). The decrease in IF and EL indicated a lowering of the behavioral-ejaculatory threshold, while the reduction in ICI and PEI indicated a stimulation of two aspects of sexual arousal. Further tests, however, revealed complexities. Using the mounting test (with genital anesthesia) as an assessment of sexual arousal, no effect of DPAT was found. Collection and examination of the coagulated ejaculates resulting from mating (copulatory plugs) provided evidence of an impairment in ejaculation, as a result of DPAT treatment. The data suggests that 5-HT1A receptor stimulation lowers the behavioral-ejaculatory threshold despite inhibition of ejaculation in and ex copula; as well as stimulating specific aspects of sexual arousal. It remains to be determined whether the effects on arousal were either due to nonselectivity as currently believed or because 5-HT1A receptor stimulation affects α2-adrenoceptor activity by some as yet undefined mechanism; and as a result modulates sexual arousal.
• Smith, E. R., Lee, R. L., Schnur, S. L., & Davidson, J. M. (1987). Alpha2-adrenoceptor antagonists and male sexual behavior: I. Mating behavior. Physiology and Behavior, 41, 7-14. doi:10.1016/0031-9384(87)90123-5
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  Three alpha 2-adrenoceptor antagonists yohimbine, idazoxan, and imiloxan were compared by examining the effects of a single injection on male rat copulatory behavior. Dose ranges were: yohimbine: 0.25-8.0 mg/kg; idazoxan: 0.25-8.0 mg/kg; imiloxan: 12.5-50.0 mg/kg. Yohimbine and idazoxan administration produced significant increases in the number of animals copulating to ejaculation and all three drugs increased the rate of copulation as evidenced by reductions in ejaculation latency and intercopulatory interval. Only yohimbine significantly reduced mount latency and postejaculatory interval, but yohimbine and imiloxan significantly reduced intromission latency and idazoxan showed a similar trend. The highest yohimbine dose suppressed sexual activity. A time-course experiment with yohimbine (2.0 mg/kg) and idazoxan (4.0 mg/kg) showed stimulation at 75 min and a trend at 5. To further explore the arousal-stimulating capacity of the two more effective drugs, a mounting test with genital anesthetization was used. Yohimbine but not idazoxan showed marked increases in mounting at 1.0-4.0 mg/kg. Both drugs had a suppressive effect at the highest doses. These data support the involvement of alpha 2-adrenoceptors in the regulation of male sexual behavior, specifically by facilitating sexual arousal, with no effects on ejaculatory threshold, as measured by intromission frequency. Yohimbine is the most globally effective agent and it is likely that factors other than yohimbine's alpha 2-antagonism may play a role in its unique, consistent and broad behavioral effects.
• Smith, E. R., Lee, R. L., Schnur, S. L., & Davidson, J. M. (1987). Alpha2-adrenoceptor antagonists and male sexual behavior: II. Erectile and ejaculatory reflexes. Physiology and Behavior, 41, 15-19. doi:10.1016/0031-9384(87)90124-7
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  Three alpha 2-adrenoceptor antagonists, yohimbine, idazoxan, and imiloxan, all shown to have stimulatory effects on sexual arousal/motivation, were studied to identify their possible effects on the other two major components of male copulatory behavior: erection and ejaculation. Genital reflex ex copula tests were used in order to assess these two responses without the confounding factors of mating behavior. Dose ranges were yohimbine: 0.25-4.0 mg/kg; idazoxan: 1.0-8.0 mg/kg; and imiloxan: 12.5-50.0 mg/kg. Lower doses of two of the drugs significantly enhanced the frequency of erections, while the third (yohimbine) showed a strong trend in that direction. At higher doses, all three alpha 2-antagonists produced significant reductions in the number of rats showing penile reflexes, including both erections and ejaculations. In those rats which did show penile reflexes, higher doses of yohimbine (4.0 mg/kg) inhibited the frequency of erections, while the higher dose of idazoxan showed a trend towards such inhibition. Thus, profound, largely inhibitory effects of these agents were demonstrated at dose ranges which have been shown to enhance sexual arousal. These data indicate that within the nervous system alpha 2-adrenoceptor antagonists can modulate erectile and ejaculatory mechanisms quite independently from effects on arousal/motivation.

Proceedings Publications

• Snyder, B., Riddell, C., Gebretsadik, T., Ding, T., Dupont, W., Ortiz, J., Lee, R., Wu, P., & Hartert, T. (2023). Leukotriene Modifying Agent Prophylaxis to Prevent Excess Morbidity and Mortality From Influenza: Two Observational Cohort Studies Using Medicaid and Department of Defense Populations Over 22 Influenza Seasons. In American Thoracic Society International Conference, 207, A6745.
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  American Journal of Respiratory and Critical Care Medicine 

Presentations

• Lee, R. (2023, June). “Health Impacts of Air Pollution”. Arizona Air Quality SummitAmerican Lung Association of Arizona.
• Lee, R. (2023, October). Designing an effective regimen for your asthma patient.  New options for asthma care.. Banner Children's Virtual Lunch-n-Learn Lecture SeriesBanner Health.
• Lee, R. (2023, September). Controlling Asthma: Going Beyond Just Daily ICS Therapy. Wheezing and Sneezing in the Desert: 17th Annual Arizona Asthma & Allergy Clinical Conference. Creighton University: Arizona Asthma Coalition.

Poster Presentations

• Ammar, L., Riddell, C. A., Ding, T., Lee, R., Maxwell-Horn, A., Snyder, B., Gebretsadik, T., & Hartert, T. V. (2024, May). Rates of respiratory syncytial virus lower respiratory tract infection among children with Down syndrome.. American Thoracic Society International Conference. San Diego, CA: American Thoracic Society.
• Ammar, L., Riddell, C., Ding, T., Lee, R. L., Maxwell-Horn, A., Snyder, B. M., Gebretsadik, T., Hartert, T. V., & Wu, P. (2023, April). Prenatal antibiotic exposure and risk of childhood asthma among children with Down syndrome.
  . Association for Clinical and Translational Science Annual meeting 2023. Washington, DC: Association for Clinical and Translational Science.
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  Objective/Goals: Children with Down syndrome are at increased risk of respiratory diseases including asthma. Prenatal antibiotic exposure has been shown to be associated with the development of childhood asthma. We aim to estimate the association between prenatal antibiotic exposure and childhood asthma among children with Down syndrome. Methods/Study Population: We conducted a retrospective cohort study of mother-child dyads of children with Down syndrome who were born 1995-2013. Both children and mothers were continuously enrolled in the Tennessee Medicaid Program (TennCare). Prenatal antibiotic exposure was measured using mother’s prescription fill records. Childhood asthma was defined between age 4.5-6 years by asthma-related healthcare encounters and asthma-specific medication fills. We assessed the association between prenatal antibiotic exposure and childhood asthma among children with Down syndrome using modified Poisson regression adjusting for maternal age, race, residence, education, marital status, smoking during pregnancy, maternal asthma status, delivery method, number of siblings, and children’s sex.   Results/Anticipated Results: Among 346 mother-child dyads of children with Down syndrome, 273 (78.9%) children were exposed prenatally to antibiotics and 104 (30.0%) had asthma by age 4.5-6 years. Among those who were exposed to at least one course, the median antibiotic course equaled 2 (interquartile range: 1-4). Prenatal antibiotic exposure was associated with a 20% increase in risk of childhood asthma in the unadjusted analysis (risk ratio [RR] 1.20, 95% confidence interval [CI] 0.78, 1.83) and a 26% increase in risk after adjustment (adjusted RR 1.26, 95% CI 0.79, 2.01). Discussion/Significance of Impact: In our study population, the majority of children with Down syndrome were exposed to antibiotics prenatally and the prevalence of asthma was high. Prenatal antibiotic exposure was associated with an increased risk of childhood asthma among children with Down syndrome; however, this increase was not statistically significant. 
• Snyder, B. M., Riddell, C. A., Bebretsadik, T., Ding, T., Dupont, W. D., Ortiz, J., Lee, R., Wu, P., & Hartert, T. V. (2023, May). Leukotriene modifying agent prophylaxis to prevent excess morbidity and mortality from influenza: two observational cohort studies using Medicaid and Department of Defense populations over 22 influenza seasons. American Thoracic Society Annual Conference. Washington, DC: American Thoracic Society.
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  Rationale: Given suboptimal influenza vaccine effectiveness, new prevention strategies for seasonal and pandemic influenza are needed. Leukotriene modifying agents (LMAs) inhibit leukotriene formation or action. They are licensed for the treatment of asthma and allergic rhinitis and can be used by people of all ages and during pregnancy. Recent animal and human studies have shown that LMAs affect respiratory virus infection and propagation. LMAs may offer a novel prophylactic approach to decrease influenza complications in humans using available, inexpensive, oral, and safe pharmacologic agents. We sought to determine the impact of LMA use among asthma and/or allergic rhinitis patients on severe influenza events.Methods: We conducted a population-based cohort study of children and adults aged 2-84 years with asthma and/or allergic rhinitis who were continuously enrolled in Tennessee Medicaid (TennCare) or the Department of Defense Military Healthcare System (DoD MHS) during at least one influenza season from 1997-2020. We employed an prevalent-user design and restricted to individuals prescribed LMA in the year prior to each influenza season to provide control for confounding by disease severity risk factors that were related to LMA use and risk factors for severe influenza. LMA protected periods were defined by prescription fill start dates plus days of supply. Severe influenza was defined as hospitalization with ICD-9/10 codes for influenza pneumonia, influenza with respiratory insufficiency, or influenza with other non-respiratory illness or organ system involvement using previously validated criteria. To estimate the causal protective effect of LMA use on amelioration of? severe influenza, we used a marginal structural model with inverse probability of treatment and censoring weights.Results: Of the 2,486,053 and 4,209,057 individuals enrolled in TennCare and DoD MHS with asthma or AR and who used LMA in the year prior to the influenza season, 516 (0.01%) and 587 (0.02%) had severe influenza, respectively. LMA use was associated with decreased risk of severe influenza in both populations (TennCare: adjusted incidence rate ratio (aIRR) 0.78 [95% confidence interval (CI) 0.62, 0.99], p=0.04; DoD MHS: aIRR 0.72, (95% CI 0.59, 0.88), p=0.001). The risk reduction was greater among individuals >65 years,

Others

• Maxa, C. (2023, November). Interviewed and quoted in news article: “Clearing the air: Lung health is inextricably linked to a person’s overall well-being.”. Arizona Daily Sun.