Nonidentical Twins With Asthma

Spatially Matched CT Airway and MRI Ventilation Abnormalities
      Recent pulmonary functional MRI findings of spatially and temporally persistent ventilation abnormalities in patients with asthma contrast with previous in silico modeling studies that suggest that in asthma, ventilation defects may be randomly distributed. In a case study that used pulmonary MRI, CT imaging, and pulmonary function tests, we prospectively evaluated over the course of 7 years, nonidentical female adult twins, each with a lifelong history of asthma. We evaluated pulmonary function and MRI ventilation heterogeneity at baseline and follow-up after 7 years. In both twins, there was a spatially identical MRI ventilation defect and an abnormal subsegmental left-sided upper lobe airway that persisted in the same spatial location after 7 years. If ventilation defects are randomly distributed, this bears a probability of approximately one per 130,000 people. Our MRI observations in related patients with asthma suggest that ventilation abnormalities may not be randomly distributed in patients with asthma and persist distal to airway abnormalities for long periods of time.

      Key Words

      Abbreviations:

      LB2 (left-sided upper lobe apicoposterior bronchopulmonary segment), RB1 (right-sided upper lobe apical bronchopulmonary segment)
      We report MRI and CT imaging findings for female adult nonidentical twins with moderate asthma who recounted a similar clinical history and symptoms of asthma since childhood, or about 40 years. In both 48-year-old women, there were spatially identical MRI ventilation defects and the same abnormal subsegmental airway, both of which remained persistently abnormal in the same spatial location over a period of 7 years.
      In patients with asthma, chronic cough, dyspnea, wheeze, and acute bronchoconstrictive worsening can be directly related to abnormal airway smooth muscle,
      • Dunnill M.S.
      • Massarella G.R.
      • Anderson J.A.
      A comparison of the quantitative anatomy of the bronchi in normal subjects, in status asthmaticus, in chronic bronchitis, and in emphysema.
      luminal inflammation and mucus plugging,
      • Hargreave F.E.
      • Nair P.
      The definition and diagnosis of asthma.
      and airway wall remodeling.
      • Postma D.S.
      • Timens W.
      Remodeling in asthma and chronic obstructive pulmonary disease.
      Pulmonary functional MRI has revealed that asthma may be expressed in a spatially heterogeneous manner, leading to MRI quantifiable ventilation heterogeneity
      • Altes T.A.
      • Powers P.L.
      • Knight-Scott J.
      • et al.
      Hyperpolarized 3He MR lung ventilation imaging in asthmatics: preliminary findings.
      • Svenningsen S.
      • Kirby M.
      • Starr D.
      • et al.
      What are ventilation defects in asthma?.
      and ventilation defects that are both spatially and temporally persistent.
      • de Lange E.E.
      • Altes T.A.
      • Patrie J.T.
      • et al.
      The variability of regional airflow obstruction within the lungs of patients with asthma: assessment with hyperpolarized helium-3 magnetic resonance imaging.
      • de Lange E.E.
      • Altes T.A.
      • Patrie J.T.
      • et al.
      Changes in regional airflow obstruction over time in the lungs of patients with asthma: evaluation with 3He MR imaging.
      Importantly and across a number of different research centers, pulmonary functional MRI has shown that in patients with asthma, ventilation abnormalities do not appear to be stochastic, nor diffusely homogeneous.
      • de Lange E.E.
      • Altes T.A.
      • Patrie J.T.
      • et al.
      The variability of regional airflow obstruction within the lungs of patients with asthma: assessment with hyperpolarized helium-3 magnetic resonance imaging.
      Such MRI findings contradict in silico modeling studies that predict randomly distributed ventilation defects in patients with asthma.
      • Venegas J.G.
      • Winkler T.
      • Musch G.
      • et al.
      Self-organized patchiness in asthma as a prelude to catastrophic shifts.
      • Tgavalekos N.T.
      • Musch G.
      • Harris R.S.
      • et al.
      Relationship between airway narrowing, patchy ventilation and lung mechanics in asthmatics.

      Case Reports

      As part of a longitudinal asthma study (ethics board No. 103516),

      Dr Grace Parraga. Structure and function MRI of asthma. NCT02351141. ClinicalTrials.gov. Bethesda, MD: National Institutes of Health; 2015. http://clinicaltrials.gov/ct2/show/NCT02351141. Updated June 26, 2018. Accessed September 5, 2019.

      we prospectively followed female twins for 2 study visits between January 2010 and March 2017 using hyperpolarized 3He MRI, thoracic CT imaging, and pulmonary function tests. Both twins were never smokers (tobacco and cannabis) and attended separate baseline visits, each reporting a longstanding diagnosis of moderate asthma according to the Global Initiative for Asthma treatment step criteria.
      Global Initiative for Asthma (GINA)
      Global Strategy for Asthma Management and Prevention: Updated 2018.
      Their clinical histories were similar; they reported that both parents were heavy tobacco smokers within the family home and both father and mother had a clinical history of airways disease. They both lived within 25 km of each other and their original family home during their lifetime. Neither twin reported occupational exposures or risk; they worked as health-care (patient 1) and day care (patient 2) providers for most of their working lives. The twins had been independently prescribed 400 μg daily dose budesonide combined with formoterol (patient 1: 200/6 μg 2 puffs once daily; patient 2: 200/6 μg 1 puff bid) by different asthma specialist care providers for the past decade. During the 7-year follow-up period, their asthma medications remained the same and there were no asthma exacerbations reported. They both reported weak-to-moderate controller medication adherence; however, both exhibited audible wheeze, exhibited shortness of breath, and reported significant exercise limitation. Both twins had airways hyperreactivity, with a provocative concentration of methacholine resulting in a 20% decrease in FEV1 of 0.08 mg/mL for patient 1 and 0.07 mg/mL for patient 2 at the baseline visit. They also demonstrated bronchodilator reversibility according to American Thoracic Society/European Respiratory Society guidelines
      • Miller M.R.
      • Hankinson J.
      • Brusasco V.
      • et al.
      Standardisation of spirometry.
      over the follow-up period (patient 1: ΔFEV1 = 260 mL, 14%; patient 2: ΔFEV1 = 220 mL, 15%). FEV1 did not change over the follow-up period for both twins (30 mL for patient 1 and 130 mL for patient 2; less than the minimal clinically important different for FEV1 in asthma
      • Santanello N.C.
      • Zhang J.
      • Seidenberg B.
      • Reiss T.F.
      • Barber B.L.
      What are minimal important changes for asthma measures in a clinical trial?.
      • Tepper R.S.
      • Wise R.S.
      • Covar R.
      • et al.
      Asthma outcomes: pulmonary physiology.
      ), and they both reported adequate asthma control (asthma control questionnaire score < 1.0).
      Figure 1 shows prebronchodilator hyperpolarized 3He MRI at baseline and follow-up, 7 years later. Magnetic resonance ventilation images provided in Figure 1 show that for both twins there was a spatially identical, focal ventilation defect at baseline; the same left-sided upper lobe ventilation abnormality also persisted at follow-up in both twins. We coregistered the follow-up MRI ventilation to the patient’s thoracic CT scan and generated 3-dimensional airway trees (Fig 1) to reveal the specific airways that corresponded to the persistent MRI ventilation defects in each patient. The posterior branch of the left-sided upper lobe apicoposterior bronchopulmonary segment (LB2) was abnormally remodeled. At follow-up, the subsegmental airway wall area percent was 71% for patient 1 and 75% for patient 2 (both of which are markedly abnormal based on the literature
      • Awadh N.
      • Muller N.L.
      • Park C.S.
      • Abboud R.T.
      • FitzGerald J.M.
      Airway wall thickness in patients with near fatal asthma and control groups: assessment with high resolution computed tomographic scanning.
      • Gupta S.
      • Siddiqui S.
      • Haldar P.
      • et al.
      Quantitative analysis of high-resolution computed tomography scans in severe asthma subphenotypes.
      ). Insets in Figure 1 provide 2-dimensional coronal CT airway subsegments, which show that LB2 was not visible distally (because of airway termination or closure) to the same extent in patient 2 as in patient 1.
      Figure thumbnail gr1
      Figure 1Spatially matched MRI ventilation defects and CT airways scans for twins with asthma. Tables show spirometry and MRI VDP at both visits and CT scan TAC and ACQ score at V2. 3He MRI ventilation (cyan) coregistered to anatomic 1H (gray scale) for the twins at two study visits, with yellow arrows showing spatially similar ventilation defects between the twins and over time. Follow-up 3-dimensional (3-D) MRI ventilation coregistered to CT scan and 3-D airway tree shows spatial relationship between left upper lobe apicoposterior segmental airway leading to similar defect, with the inset showing airway segment on CT scan. White arrows show spatially persistent airways in 3-D and in 2-dimensional CT scan insets. ACQ = asthma control questionnaire; TAC = total airway count; V1 = baseline, visit 1; V2 = follow-up, visit 2; VDP = ventilation defect percent.
      We also coregistered the airway trees to directly compare the twins’ overall tree, as shown in Figure 2. The bulk airway anatomy was similar, with differences mainly in branching angles. Notably, patient 2 had fewer airways overall than patient 1 (total airways count, 166 vs 202, respectively). This is reflected in the number of airways by airway tree generation distal to LB2 and right-sided upper lobe apical bronchopulmonary segment (RB1). Wall area percent at the generation of the LB2 airway spatially related to the persistent ventilation defect (Fig 2, asterisk) was increased relative to RB1 (as a comparator) in both twins.
      Figure thumbnail gr2
      Figure 2Coregistered CT scan airway trees. Coregistered airway trees for patient 1 (dark blue) and patient 2 (light blue) show similar bulk airway anatomy. Airway trees were registered to align LB2 and comparator RB1 (zoomed, arrows), and corresponding n and mean WA% by airway tree generation are shown for both segments. Asterisks in the table indicate generation of abnormally remodeled LB2 airway that corresponds to the spatially persistent defect between the twins. LB2 = left upper lobe apicoposterior bronchopulmonary segment; n = number of airway branches; RB1 = right-sided upper lobe apical bronchopulmonary segment; WA% = wall area percent.

      Discussion

      A number of MRI investigations of asthma point to gas distribution abnormalities that are spatially and temporally persistent, suggestive of ventilation heterogeneity that is spatially nonrandom and preserved over time. We wondered about the likelihood of twins with asthma having identical MRI ventilation defects that could be identified as related to abnormal airways measured using CT imaging; we also wondered if such abnormalities might also persist after a long period of time in patients with asthma with relatively stable disease.
      If we assume that ventilation abnormalities are randomly distributed, to estimate the probability of two participants with asthma having the same segmental ventilation defect over a relatively long period of time, we considered the 19 anatomically and functionally distinct bronchopulmonary segments and made the following assumptions: (1) both patients with asthma would report at least one ventilation defect and no more than one defect per bronchopulmonary segment (ie, > 0 and < 19 ventilation defects),
      • de Lange E.E.
      • Altes T.A.
      • Patrie J.T.
      • et al.
      Evaluation of asthma with hyperpolarized helium-3 MRI: correlation with clinical severity and spirometry.
      and (2) there was an equivalent probability for each of the 19 bronchopulmonary segments to express a ventilation defect. We assumed that each of the twins would have at least one ventilation defect because of their longstanding clinical asthma diagnosis of asthma and their age.
      • de Lange E.E.
      • Altes T.A.
      • Patrie J.T.
      • et al.
      Evaluation of asthma with hyperpolarized helium-3 MRI: correlation with clinical severity and spirometry.
      Patients with asthma with MRI ventilation defects are typically older than patients with asthma without defects,
      • Svenningsen S.
      • Kirby M.
      • Starr D.
      • et al.
      What are ventilation defects in asthma?.
      and the presented twins were older than the mean age of participants in this previously reported investigation (35 ± 11 years of age).
      • Svenningsen S.
      • Kirby M.
      • Starr D.
      • et al.
      What are ventilation defects in asthma?.
      We first observed one ventilation defect in the apicoposterior left-sided upper lobe segment in patient 1, and the probability for this single defect in this single bronchopulmonary segment was one in 19. Following this estimate, the probability that patient 2 would have exactly one defect in the same bronchopulmonary segment was one in 192 or one in 361.
      Mathematical models of asthmatic airways predict that ventilation or gas distribution abnormalities would be random or stochastic.
      • Venegas J.G.
      • Winkler T.
      • Musch G.
      • et al.
      Self-organized patchiness in asthma as a prelude to catastrophic shifts.
      • Tgavalekos N.T.
      • Musch G.
      • Harris R.S.
      • et al.
      Relationship between airway narrowing, patchy ventilation and lung mechanics in asthmatics.
      • Tgavalekos N.T.
      • Tawhai M.
      • Harris R.S.
      • et al.
      Identifying airways responsible for heterogeneous ventilation and mechanical dysfunction in asthma: an image functional modeling approach.
      If we assume that the occurrence of ventilation defects in asthma was random over time, such that the presence and spatial locations of ventilation abnormalities appeared in different lung segments over time, we could also determine the probability that two patients have the same single segmental ventilation defect at baseline and again at 7-year follow-up to be one in 194 or one in 130,321. These odds are less likely than a single individual’s risk of being struck by lightning (approximately one in 10,000 in a lifetime and one in 100,000 annual risk) and suggest that MRI ventilation defects may not be randomly distributed. Although MRI studies have shown that the presence and size of specific ventilation defects may fluctuate modestly over time,
      • de Lange E.E.
      • Altes T.A.
      • Patrie J.T.
      • et al.
      Changes in regional airflow obstruction over time in the lungs of patients with asthma: evaluation with 3He MR imaging.
      • Svenningsen S.
      • Guo F.
      • Kirby M.
      • et al.
      Pulmonary functional magnetic resonance imaging: asthma temporal-spatial maps.
      MRI ventilation defects in participants with asthma are mainly spatially persistent. In both twins, there was evidence of airways hyperreactivity and bronchodilator reversibility through the follow-up period; therefore, the abnormal remodeling of the apicoposterior left-sided upper lobe airway may stem from increased airways smooth muscle mass. However, we cannot comment on the contribution of airway inflammation because it was not evaluated. Longitudinal MRI and CT studies in patients with asthma have demonstrated persistent and dynamic disease components,
      • de Lange E.E.
      • Altes T.A.
      • Patrie J.T.
      • et al.
      Changes in regional airflow obstruction over time in the lungs of patients with asthma: evaluation with 3He MR imaging.
      • Svenningsen S.
      • Guo F.
      • Kirby M.
      • et al.
      Pulmonary functional magnetic resonance imaging: asthma temporal-spatial maps.
      • Witt C.A.
      • Sheshadri A.
      • Carlstrom L.
      • et al.
      Longitudinal changes in airway remodeling and air trapping in severe asthma.
      • Dunican E.M.
      • Elicker B.M.
      • Gierada D.S.
      • et al.
      Mucus plugs in patients with asthma linked to eosinophilia and airflow obstruction.
      whereas here we focused on persistently abnormal regions. For example, patient 1 exhibited ventilation heterogeneity in the right-sided lung base that was not present at follow-up, which was the same in patient 2. These regions of abnormal ventilation were associated with abnormally remodeled airways (patient 1: right-sided lower lobe lateral basal bronchopulmonary segment and right-sided lower lobe posterior basal bronchopulmonary segment most distal branches mean wall area percent, 68% generation 5 vs LB2 mean wall area percent, 71% generation 6). We think that intermittent ventilation abnormalities may be caused by transient inflammation in combination with airway remodeling; however, inflammatory status was not evaluated.
      Limitations of our case study and analysis include that the twins were only evaluated twice and the assumption we made that there was an equal probability of ventilation defects appearing in any of the 19 bronchopulmonary segments. In other words, we did not take into consideration that in twins, there might be a bias for airways and ventilation abnormalities in specific lung regions. In addition, we did not make any assumptions about a potential upper limit for ventilation defect number, less than the 19 potential segmental airways. However, in our experience in > 200 patients with asthma, there are typically fewer than five ventilation defects in participants with moderate disease, which is consistent with previous investigations.
      • de Lange E.E.
      • Altes T.A.
      • Patrie J.T.
      • et al.
      Evaluation of asthma with hyperpolarized helium-3 MRI: correlation with clinical severity and spirometry.
      Therefore, the probability of repeated defects in space and time as we observed would be lower; therefore, our estimates are conservative. A more rigorous analysis could include the probability of multiple ventilation defects, the probability of twins having asthma, or the probability of subsegmental (38 subsegments) or sub-subsegmental (76 sub-subsegments) ventilation defects, all of which would serve to lower the probabilities estimated here. Finally, we have assumed the persistent ventilation defect in these patients to be related to asthma pathophysiology and/or abnormal airway structure. These findings could also be explained to some extent by shared genetics, epigenetics, or in utero events, which we did not evaluate here and cannot rule out.
      In twins with asthma, we observed a single spatially identical MRI ventilation defect related to abnormal airway remodeling which persisted in the same spatial location after 7 years. If ventilation defects occur randomly in patients with asthma, the probability of this occurring in both patients in the same location, twice over 7 years, is approximately one in 130,000 people.

      Acknowledgments

      Financial/nonfinancial disclosures: The authors have reported to CHEST the following: G. P. has received consulting fees from Novartis AG (2019) and received study funding from Astra Zeneca PLC, neither of which were related to this work. None declared (R. L. E., A. M. M., S. S., D. K., C. L., D. G. M.).
      Role of sponsors: The sponsor had no role in the design of the study, the collection and analysis of the data, or the preparation of the manuscript.
      Other contributions: CHEST worked with the authors to ensure that the Journal policies on patient consent to report information were met.

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