(Radiology. 1999;210:815-822.)
© RSNA, 1999
Radioaerosol Scintigraphy in Infants and Children Born to Mothers with HIV Disease
Philip O. Alderson, MD1,
David C. P. Chen, MD3,
Matthew J. Fleishman, MD1,
Carl K. Hoh, MD4,
Chun K. Kim, MD5,
Victor W. Lee, MD6,
Robert B. Mellins, MD2,
John H. Miller, MD7,
Warren H. Moore, MD8,
Hannah H. Peavy, MD9,
Amrik Shah, MD10 and
S. Ted Treves, MD1,11
1 From Depts of Radiology (P.O.A., M.J.F.)
2 Pediatrics (R.B.M.), Columbia-Presbyterian Medical Center, 622 W 168th St, New York, NY 10032
3 Dept of Radiology, Univ of Southern California Medical Center (D.C.P.C.)
4 Dept of Radiology, Univ of California, Los Angeles Medical Center and School of Medicine (C.K.H.)
5 Dept of Radiology, Mount Sinai Medical Center and School of Medicine, New York (C.K.K.)
6 Dept of Radiology, Boston City Hospital, Mass (V.W.L.)
7 Dept of Radiology, Children's Hospital, Los Angeles, Calif (J.H.M.)
8 Dept of Radiology, Texas Children's Hospital, Houston (W.H.M.)
9 Div of Lung Diseases, National Heart, Lung and Blood Institute, Bethesda, Md (H.H.P.)
10 Dept of Biostatistics and Epidemiology, Cleveland Clinic, Ohio (A.S.)
11 Div of Nuclear Medicine, Children's Hospital, Harvard Medical School, Boston, Mass (S.T.T.).
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Abstract
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PURPOSE: To determine the usefulness of technetium 99m diethyltriaminepentacetic acid (DTPA) radioaerosol inhalation-clearance scintigraphy for early detection of pulmonary complications of human immunodeficiency virus (HIV) disease in children.
MATERIALS AND METHODS: A total of 301 studies were performed in 132 HIV-positive children (group 1; mean age, 46.6 months). In children born to HIV-positive mothers (group 2), 273 studies were performed in 160 children who eventually were proved to be HIV negative (mean age, 10.3 months), and 80 studies were performed in 47 HIV-positive children (mean age, 15.6 months). Radioaerosol studies were performed by using commercially available radioaerosol nebulizers. Pulmonary clearance half-time was measured by using conventional gamma camera computer systems. Radioaerosol results were correlated with indexes of pulmonary health and function.
RESULTS: The HIV-negative, group 2 children had a mean radioaerosol clearance half-time (58.1 minutes; 162 studies in 108 children) similar to that reported in healthy adults. Group 1 children with pulmonary involvement exhibited a faster mean clearance half-time (28.6 minutes) than did children without evidence of pulmonary involvement from either group 1 or group 2 (P < .05). A faster pulmonary clearance rate did not simply reflect the presence of chest disease that also was detectable on radiographs (P = .3).
CONCLUSION: Quantitative DTPA radioaerosol clearance studies may provide useful information about pulmonary involvement in selected children with HIV disease.
Index terms: Acquired immunodeficiency syndrome (AIDS), 60.2518 • Lung, diseases, 60.2518 • Lung, radionuclide studies, 60.12176 • Lung, ventilation
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Introduction
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Shortly after the initial description of the acquired immunodeficiency syndrome (AIDS), cases were described in infants and children (1–3). Vertical transmission of the human immunodeficiency virus (HIV) from an infected mother to an infant accounts for the majority of these cases and is reported (4) to occur in 15%–30% of all the births to untreated women. Cardiopulmonary disease contributes substantially to the morbidity and mortality associated with pediatric AIDS. This was the basis for a multiinstitutional, prospective, natural history study, sponsored by the National Institutes of Health (Bethesda, Md) and begun in 1989, of cardiopulmonary complications of this disorder (5). One of the goals of the study was to determine whether potentially serious HIV-associated pulmonary disease could be detected before it became clinically evident in these children and to evaluate what effect, if any, such early detection might have on the natural history of the disorder.
A variety of pulmonary function–related examinations were performed periodically in both HIV-positive and HIV-negative populations. The tests included chest radiography and technetium 99m diethyltriaminepentacetic acid (DTPA) radioaerosol inhalation-clearance rate studies. Radioaerosol inhalation imaging has been used in children for more than 20 years and has been used safely and successfully in neonates (6–8). Soluble radioaerosols such as 99mTc DTPA clear from the lung quickly and predominantly by means of transalveolar absorption with low pulmonary radiation exposures. These aerosols have become recognized as a sensitive means for studying the integrity of the pulmonary epithelium (9). Accordingly, quantitative 99mTc DTPA radioaerosol inhalation-clearance scintigraphy was chosen as one of the pulmonary diagnostic studies to be used in these prospective natural history studies of vertically transmitted pediatric HIV infection. The purpose of the current study was to determine if 99mTc DTPA radioaerosol scintigraphy could be used to detect and quantify the severity of HIV-associated disease in this population.
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MATERIALS AND METHODS
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Patient Population
The organizational and epidemiologic details of this multiinstitutional prospective study have been described in detail (5). In brief, after institutional review board approval and informed consent were obtained, teams of investigators at five clinical centers recruited HIV-positive pregnant women from obstetric clinics attended by high-risk patients and known HIV-positive children from hospital pediatric clinics and inpatient units. The goal was to achieve a statistically appropriate cohort of infants and children already known to have vertically transmitted HIV infection (group 1) and a cohort of infants born to HIV-infected mothers (group 2). Group 1 subjects had to be born after April 1, 1985, have documented evidence of vertically acquired HIV, and be more than 28 days old. Group 2 subjects typically were designated for the study during gestation. If not, they had to be enrolled before they were 28 days old. Later, group 2 subjects were assigned to group 2a (infected) or group 2b (noninfected). The assignment of the child to the HIV-positive (infected) group required two positive HIV cultures. Two negative cultures (and no positive cultures), with one occurring at 5 months of age or older were necessary for assignment to the HIV-negative (uninfected) group. Further confirmation of HIV-negative status was obtained on the basis of enzyme-linked immunosorbent assay results and, if necessary, Western blot results in all HIV-negative patients at a minimum age of 15 months. Ultimately, 205 group 1 infants and children and 600 live-born group 2 infants were recruited. Vigorous efforts were made to perform 99mTc DTPA radioaerosol inhalation-clearance scintigraphy on as many of the enrolled children as possible.
Radioaerosol Studies
The 99mTc DTPA radioaerosol inhalation studies were performed at each participating institution by using procedural standards agreed to beforehand. A total of 656 radioaerosol studies were performed in 341 infants and children. 99mTc DTPA (5 mg; Bristol Meyers–Squibb, New Brunswick, NJ) was used to create the radioaerosols by mixing 740–1,100 MBq of activity with 3 mL of normal saline solution in commercial radioaerosol nebulizers (Cadema Medical Products, Middleton, NY; or Syntevent, Palo Alto, Calif) designed to deliver a submicrometer polydisperse radioaerosol. Air flow to the nebulizer was set at 8–10 L/min. In infants and children younger than 2 years, who accounted for the majority of patients in the current study, the radioaerosol was administered by directing the tubing from the nebulizer to the reservoir of an Ambu bag attached to a tightly fitting plastic pediatric face mask. The child lay supine over the face of an inverted gamma camera with his or her neck slightly extended. The cameras were interfaced to existing data acquisition computers in each laboratory. Attempts were made to coordinate puffs from the bag with the inspiratory phase of crying or normal breathing. In older and more cooperative children, radioaerosol was delivered by means of a standard mouthpiece pipe, with nasal pincers or parental assistance used to occlude the nares. Radioaerosol inhalation was continued with a target pulmonary count rate of at least 50,000 counts per minute. This was not always achieved, especially in infants. In such instances, the lowest count rates accepted were approximately 10,000 counts per minute. On the basis of the theoretic pulmonary deposition of approximately 25–30 MBq in the lungs, the prestudy estimate of pulmonary radiation exposure was in the order of 400–500 mrad (4–5 mGy). For this calculation, we assumed a pulmonary clearance half-time of 60 minutes. No other types of radionuclide studies (eg, perfusion scans) were obtained in this protocol.
After inhalation of 99mTc DTPA, radioaerosol administration was terminated, and the nebulizer tubing was disconnected from the mask or mouthpiece. At this point, the computerized acquisition of radioaerosol clearance data began. One hundred twenty frames of 15-second duration in a 128 x 128 matrix were acquired and displayed as an aerosol clearance curve. All reasonable attempts to prevent substantial patient motion were made during the 30-minute data acquisition phase. The presence of excessive motion was assessed primarily by reviewing the clearance-phase time-activity curves and by looking for sudden discontinuities. When such discontinuities were judged to be important, the studies were excluded. The clearance data curves were derived from a hand-drawn region of interest over images derived from the 1st minute of data acquisition, but all images (1–30 minutes) were inspected. Regions of interest were drawn separately around each whole lung (Fig 1). Care was taken to exclude regions of perihilar hyperdeposition, as well as central regions that showed tracheal or esophageal activity. Care also was taken to adjust the left lung base region of interest to be superior to the zone of swallowed gastric radioactivity, which was a variable but common finding, especially on later data frames. Regions of interest also were hand drawn subjectively over the peripheral one-third of each lung in an attempt to derive data from a "pure" alveolar zone. Unfortunately, the counts in the majority of these peripheral regions of interest were too low, and these attempts were abandoned.
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Figure 1. Posterior 99mTc DTPA radioaerosol image obtained over the thorax at the end of the inhalation period. This 4 -year-old boy in group 1 had a relatively benign course and was alive 5 years after this study was obtained. Regions of interest (solid and dotted lines) outline each lung. Deposition in the lungs is uniform. A chest radiograph obtained the previous day (not shown) showed clear lungs. The 99mTc DTPA clearance half-time was 56.5 minutes, which is normal.
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Data Analysis
Analysis of 99mTc DTPA clearance curves was performed by using the method of O'Brodovich and Coates (10), in which the egress rate of radioaerosol is determined by means of a least-squares single exponential fit to the early portion of clearance data. At this early time, there is little extrapulmonary activity accumulation, so background subtractions are not necessary (11). In the 1st year of the study, the group also evaluated a similar exponential fit to the first 30 minutes of clearance data. Inconsistencies in background activity and subtraction techniques between laboratories led to discontinuation of this aspect of the clearance data analysis. All reported clearance data are based on early, 8-minute collection periods without background subtraction.
Completed studies were reviewed on site to grade the uniformity of deposition, because patchy peripheral deposition may be a marker of localized pulmonary disease. The images and data curves then were generated and delivered to the Columbia-Presbyterian Medical Center (New York, NY) for a thorough quality-control review. This review was performed by using a data form that required the reviewer (P.O.A.) to record his subjective impressions of overall image quality by using a five-point scale in which a score of 1 was assigned for excellent quality and a score of 5 was assigned for unacceptable. The presence and degree of central radioaerosol hyperdeposition (Fig 2) and tracheal and gastric radioactivity were graded as follows: 1, minimal; 2, mild; 3, moderate; or 4, severe. The shape of the clearance curve also was analyzed for the presence of sharp discontinuities, unusual shapes, or poor statistical quality. Adherence of each center to similar regions of interest and uniform approaches to fitting clearance curves was documented by means of a quality review of images on which the regions of interest were inscribed, as well as by a review of the clearance curves themselves. During this centralized quality review and during all phases of clearance curve analysis, the reviewers were blinded to the data group (ie, 1, 2a, 2b) of the patient study being analyzed. Although children in group 2b (HIV negative) cannot strictly be considered to be healthy, these children served as the age-matched normative database for comparison with the HIV-infected patients.
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Figure 2a. (a) Posterior 99mTc DTPA radioaerosol image obtained over the thorax at the end of the inhalation period. This 10-month-old group 1 male infant was studied approximately 2 months before the onset of a terminal illness that included respiratory distress and sepsis. Peripheral deposition of 99mTc DTPA was uniform, but there was moderate central airway hyperdeposition (arrowheads). The outlined regions of interest were modified to avoid these areas. (b) Graph of clearance analysis data reveals accelerated 99mTc DTPA egress (half-time [T1/2], 27.9 minutes). The dotted line represents the clearance function fit to the first 8 minutes of data; the solid line represents the actual data. There was no chest radiograph obtained near the time the radioaerosol study was obtained.
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Figure 2b. (a) Posterior 99mTc DTPA radioaerosol image obtained over the thorax at the end of the inhalation period. This 10-month-old group 1 male infant was studied approximately 2 months before the onset of a terminal illness that included respiratory distress and sepsis. Peripheral deposition of 99mTc DTPA was uniform, but there was moderate central airway hyperdeposition (arrowheads). The outlined regions of interest were modified to avoid these areas. (b) Graph of clearance analysis data reveals accelerated 99mTc DTPA egress (half-time [T1/2], 27.9 minutes). The dotted line represents the clearance function fit to the first 8 minutes of data; the solid line represents the actual data. There was no chest radiograph obtained near the time the radioaerosol study was obtained.
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Data compilation and statistical analyses were performed at the data coordinating center. General statistical techniques included use of paired Student t tests, analysis of covariance, and linear regression analysis. Right lung and left lung data were correlated to investigate the validity of reliance on clearance data from the right lung alone when counts and clearance curves obtained from the base of the left lung were compromised owing to scattered radioactivity from the adjacent stomach or because of other artifacts.
The DTPA studies for group 1 and 2 children were temporally matched with clinical signs of pulmonary disease—namely, crackles, clubbing, and tachypnea—and with oxygen saturation measured at pulse oximetry. Together, these markers served as the reference standard for the presence of pulmonary disease. An acceptable window for matching the DTPA studies with abnormal or normal clinical findings was 7 days either before or after the DTPA study. For children with multiple acceptable studies, we gave priority to an abnormal finding if available. Otherwise, the study with the smallest "window" (nearest in time to the clinical diagnosis) was used. The DTPA clearance times also were examined. Clearance half times greater than 125 minutes, which were infrequent (both lungs n = 11, right lung n = 5), were considered to be spurious and were not included in the analysis. Comparison of DTPA clearance half-times between groups was performed by using repeated measures analysis, with age and group as factors along with a subject-specific random effect (statistical software manufacturer's recommendation; SAS Institute, Cary, NC).
The results from pulse oximetry also were compared with the 99mTc DTPA clearance rates. Pulse oximetry was performed in group 1 children at the initial pulmonary visit and at every routine pulmonary visit thereafter; it was performed in the group 2 children at the time of birth and at every routine pulmonary visit thereafter. A patient was deemed to have abnormal arterial oxygen saturation as measured at pulse oximetry if he or she had at least one (from all visits) abnormal oxygen saturation reading (<96%). For each visit, if the initial oxygen saturation reading was equivocal (96% or 97%), a second reading was obtained and used. A repeated measures model with oxygen saturation status as an independent predictor was used to determine the association with half-time clearance times for both lungs and for the right lung alone.
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RESULTS
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Study Population
The children who participated in the DTPA studies were quite young, and the group 2 children were significantly (P < .05) younger than those in group 1 (Table 1), as might be expected on the basis of their respective entry paths into the study. The overall frequency of pulmonary disease in the DTPA study group as reflected by at least one abnormal oxygen saturation reading per child is given in Table 2A. The percentage of abnormal oxygen saturation findings (based on all tests performed) was similar among those who underwent DTPA studies and the overall study population (Table 2B).
A total of 301 DTPA studies were performed in group 1 children, and 355 were performed in group 2 children (80 in group 2a, 273 in group 2b, two in children whose HIV status was undetermined). These were performed in 132 group 1 children and 209 group 2 children (47 in group 2a, 160 in group 2b, two in children whose HIV status was undetermined). The requisite data were available for quality review of the DTPA studies in 556 (85%) of the 656 studies performed (249 in group 1, 70 in group 2a, 235 in group 2b, and two in HIV-indeterminate children). On the basis of this review, a total of 399 studies (72%) were judged to be of acceptable quality. These included 191 studies in group 1 children and 208 in group 2 children (46 in HIV-positive and 162 in HIV-negative children). When the criteria for technical quality were applied only to the right lung, the number of acceptable studies increased to 406 (78.8%), which included 194 in group 1 children and 232 in group 2 children (51 in HIV-positive and 181 in HIV-negative children). The average age (±SD) of group 2 children with satisfactory studies was 10.9 months ± 5.4 (41 studies), whereas the average age of children with technically unacceptable studies was 14.5 months ± 10.9 (188 studies) (P < .05).
Common technical problems included partial interference with pulmonary clearance calculations by radioactivity in the stomach secondary to swallowed 99mTc DTPA. Such radioactivity was seen in 78 (33.6%) of 232 group 2 studies for which quality assurance data were available and necessitated upward adjustment of the left lower lobe region of interest. In group 2, swallowed gastric radioactivity was especially common in DTPA studies in children without HIV infection who were younger than 1 year of age (129 [85.4%] of 151). Perihilar central deposition of inhaled radioaerosol was seen on 191 studies (minimal, n = 74; mild, n = 52; moderate, n = 37; severe, n = 28) and necessitated modest adjustment of the perihilar regions of interest in 74 (39.6%) of 187 cases with completed forms. Midline activity above the hilar region also was seen but rarely required an adjustment of any region of interest. Low midline activity in the esophagus near the gastric junction was rare. Excessive patient motion was a problem in only 13.8% of studies.
DTPA Aerosol Findings
Clearance rate data from both lungs were satisfactory for quantitative analysis of DTPA clearance in 399 studies. The group classification, age, and clearance data for the first 21 months of follow-up (n = 346) in these patients are given in Table 3. Similar data for the first 21 months of follow-up were derived by using the right lung and were able to be analyzed in 370 studies (Table 4). Data were limited to the first 21 months of follow-up, because few patients had studies beyond this time. By using the results of the first (acceptable) study from each group 2 child tested, the correlation coefficient for right and left lung clearance (143 pairs) was 0.77 (P < .01). 99mTc DTPA clearance was significantly faster in children who had established HIV infection at the time of enrollment (group 1) than in those who were HIV negative (group 2b). These differences were seen in the 3–9-month age groups (n = 187) when DTPA clearance was calculated from the average of both lungs (P < .05) (Table 3). The results for right lung (only) clearance (not shown) yielded similar conclusions.
In the subset of 554 reviewed group 1, group 2a, and group 2b studies, the distribution of activity in lung fields was nonuniform in 134 (24.2%) studies (Fig 3). Of these 134 studies, 49 were in the noninfected group, 64 were in the group known to have HIV when enrolled (group 1), and 21 were in HIV-infected children who were enrolled at birth (group 2a). In both groups, patients with nonuniform parenchymal radioaerosol deposition had shorter 99mTc DTPA clearance half-times. In group 1, the mean 99mTc DTPA clearance half-time (±SD) for both lungs in patients with nonuniform deposition was 33.3 minutes ± 30.2 (63 studies) versus 42.9 minutes ± 52.2 (173 studies) in patients judged to have uniform deposition (P > .5). In group 2a (HIV-infected) children, the DTPA clearance half-time for both lungs with a uniform 99mTc DTPA distribution was significantly slower, that is, more like normal (63.5 minutes ± 47.8, n = 46) than it was in children with a nonuniform distribution (38.9 minutes ± 29.4 min, n = 21, P = .01).
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Figure 3a. (a) Posterior radioaerosol image obtained over the thorax at the end of the inhalation period. This group 1 10-year-old girl had a markedly abnormal chest radiograph (not shown) obtained 4 days before the 99mTc DTPA study. The radiograph depicted diffuse, bilateral, reticular areas of intense opacification and increased lung volume. The 99mTc DTPA deposition is markedly inhomogeneous, with numerous bilateral peripheral "hot spots." (b) Graph shows that the clearance half-time (T1/2) of 99mTc DTPA was rapid (20.6 minutes). The dotted line represents the clearance function fit to the first 8 minutes of data; the solid line represents the actual data. This patient had wasting syndrome and sepsis and died 10 months later.
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Figure 3b. (a) Posterior radioaerosol image obtained over the thorax at the end of the inhalation period. This group 1 10-year-old girl had a markedly abnormal chest radiograph (not shown) obtained 4 days before the 99mTc DTPA study. The radiograph depicted diffuse, bilateral, reticular areas of intense opacification and increased lung volume. The 99mTc DTPA deposition is markedly inhomogeneous, with numerous bilateral peripheral "hot spots." (b) Graph shows that the clearance half-time (T1/2) of 99mTc DTPA was rapid (20.6 minutes). The dotted line represents the clearance function fit to the first 8 minutes of data; the solid line represents the actual data. This patient had wasting syndrome and sepsis and died 10 months later.
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Correlations between DTPA Aerosol Results and Lung Function
Correlations were weak between 99mTc DTPA clearance and other individual measures of lung function. There was no significant correlation with arterial oxygen saturation alone (results not shown) in either group 1 or group 2. There was a significant (P < .05) correlation in group 1 children between accelerated DTPA clearance rates and the presence of any one of the following signs: auscultatory crackles (localized or general), finger clubbing, tachypnea, or abnormal oxygen saturation (Table 4). However, these same relationships could not be demonstrated in group 2 children (P = .31–.41). In addition, the DTPA clearance half-times were not significantly correlated (P > .3) with the presence of chest radiographic abnormalities (not shown).
Normative Group
The normative group—that is, children enrolled at birth who eventually proved to be HIV negative (group 2b)—was assessed for associations between DTPA clearance and age. No significant relationship (P = .7) was found, however. When using clearance either from both lungs or only from the right lung, the intrasubject variations were larger than the intersubject variations, and the intraclass correlation coefficients were low (0.19 and 0.25 for the right lung only and for both lungs, respectively). The mean DTPA clearance half-time for this entire normative group (162 studies), which included children aged 5.1–22.0 months, was 58.1 minutes ± 63.6.
Early Detection of Substantial Pulmonary Disease
Of the 31 children with a vertical infection who were enrolled at birth (group 2a), 10 died during the period of observation. The baseline mean right lung DTPA clearance half-time in these children was 31.7 minutes ± 12.5. In the 21 children in this group who survived, the mean clearance time was 57.6 minutes ± 53.4. There was no significant difference in mean age at the time of testing of the children in these two subgroups (47.8 weeks in those who survived vs 40.7 weeks in those who did not, P = .52). Although the clearance rate differences seemed potentially important, a Cox regression model for comparing the DTPA clearance times between children who survived and those who did not was not significant (P = .14). Pulmonary radiographic abnormalities were present in eight of the 10 group 2a children who died versus 15 of 21 in the children who survived (P = .6).
To evaluate further the usefulness of accelerated DTPA clearance as an early predictor of pulmonary disease, 67 children were evaluated who underwent DTPA studies before undergoing one or more pulmonary function test sessions. Of 22 patients who had an accelerated clearance half-time of less than or equal to 20 minutes, eight patients later developed pulmonary disease (average follow-up, 30 weeks; range, 16–56 weeks). The other 14 patients did not develop pulmonary disease during a follow-up that averaged 44 weeks. Nine of 45 patients with a DTPA clearance half-time of longer than 20 minutes (average, 48.5 minutes) also developed pulmonary disease. The sensitivity of DTPA study results for early prediction in this subset of the population was 47%, and the specificity was 72%. The negative predictive value was 80%, and the positive predictive value was 57%.
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DISCUSSION
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Pulmonary involvement is important in patients with AIDS, the lungs often being the site of what is eventually a life-threatening illness (12). Lymphocytic infiltrates of the alveolar septa occur much more commonly in children with AIDS than in adults with AIDS (13,14). This lymphocytic interstitial pneumonitis may be the initial manifestation of the disorder and may progress to a frank exudative alveolitis. As this process advances, increased interstitial markings become visible on radiographs, but this is not true in the earlier stages. Later in the course of lung involvement in children, specific infections such as Pneumocystis carinii or cytomegalovirus pneumonia predominate (15). At some point during this evolving pneumonitis, there is a stage when chest radiographs are normal, but radionuclide studies of inflammation such as gallium 67 scintigraphy (16) and indium 111 white blood cell studies (17) are abnormal—at least in adults.
In the current study, we sought to determine whether detection at earlier stages was possible by using a scintigraphic method that reflected the integrity of the alveolar-capillary membrane rather than the presence of inflammatory cells. If lymphocytic interstitial pneumonitis or other types of nonspecific alveolitis are the earliest manifestations of pulmonary involvement in pediatric HIV disease (13), then 99mTc DTPA transalveolar clearance rate scintigraphy could potentially provide a means for early discrimination of children at the greatest risk for pulmonary complications. Although we realized that 99mTc DTPA inhalation studies would be more difficult to perform than scintigraphic studies that relied on intravenous injection of tracers, the radiation dose from inhalation scintigraphy is much lower than that received from 67Ga citrate or 111In white blood cell studies. The combination of low radiation exposure and potentially earlier diagnosis suggested that 99mTc DTPA inhalation studies should be investigated.
Studies of 99mTc DTPA inhalation and clearance have been widely used to investigate disorders of the alveolar-capillary membrane in adults (9,18). Transalveolar clearance of 99mTc DTPA is thought to be primarily diffusion related, with pulmonary arterial blood flow being only a minor determinant of clearance rates at the extremes of blood flow abnormality. Increased access of 99mTc DTPA to the alveolar-capillary membrane through the fluid-surfactant layer of the epithelial lining (18) yields higher rates of egress, as does exposure to large alveolar absorptive areas, given that other conditions are constant. Early inflammation of the alveolar interstitium and/or epithelium would be expected to yield accelerated 99mTc DTPA clearance rates. Later, as alveolar exudation and pulmonary congestion increase, clearance would paradoxically be prolonged by the lack of 99mTc DTPA access to the alveolar absorptive surface.
The results of the current study confirm the technical feasibility of 99mTc DTPA studies in infants. Technically satisfactory radioaerosol studies were obtained in approximately 72% of the population. Given appropriate technical skills and access to conventional scintigraphic instruments, it should be possible to perform these studies in infants and children at most institutions. Infants adjusted well to the Ambu bag method of radioaerosol administration.
Excessive perihilar radioaerosol deposition, a source of concern in adults who undergo radioaerosol inhalation scintigraphy (19,20), was not a major problem in the infants and children in the current study. Swallowed radioaerosol activity in the stomach was a much more common problem, especially in infants. Accumulation of radioaerosol in the stomach over time created difficulties when a region of interest was outlined too low on the left lung prior to the eventual appearance of substantial gastric radioactivity in that same region. This is the reason that the usefulness of right lung determinations of 99mTc DTPA clearance was evaluated. Swallowed radioactivity was particularly common in infants. If radioaerosol scintigraphy was to be used to provide prognostic information in this age group, the current results suggest it would be reasonable to constrain the DTPA clearance analysis to the right lung when excess gastric activity or other problems potentially interfere with left lung data.
The data from group 2 infants who eventually proved to be free of HIV provided a normative base against which to compare infants with an unknown HIV status. There were concerns, however, that growth and lung development within the ages represented in this subset of the study (3–21 months) might be an important source of scatter in the data. Davies and Reid (21) studied pediatric autopsy specimens and reported that both the size and number of alveoli in young children were smaller than those in adults. The number of alveoli continues to increase until about the age of 8 years, at which time the increase in numbers plateaus, and individual alveoli begin to expand. In the young population evaluated in this study, there were no age-related changes in 99mTc DTPA pulmonary clearance rates. The mean clearance half-time in this group (58.1 minutes) was quite similar to that reported in adults in a number of other studies (9). It also was somewhat slower than the clearance rates reported by O'Brodovich and Coates (8) in infants recovering from hyaline membrane disease. The patients in the current normative group, however, were probably somewhat healthier than the patients in the study of O'Brodovich and Coates.
The results of the current studies suggest that accelerated 99mTc DTPA clearance rates may provide a method for early detection of pulmonary HIV disease in certain subsets of children. The data also show that 99mTc DTPA pulmonary clearance study results are not directly related to chest radiographic findings. This suggests that an unspecified type of preclinical alveolitis existed in infants with accelerated DTPA clearance. A sensitive test of pulmonary epithelial integrity, although nonspecific, could provide the opportunity for early detection of and intervention for pulmonary involvement in HIV disease in infants and young children. The technical skills exist to perform and analyze the studies, but the amount of work involved suggests that they should not be used as screening tests. In selected infants in whom the clinical suspicion of pulmonary involvement is high but unconfirmed or in older children whose pulmonary status changes without an obvious reason, quantitative 99mTc DTPA radioaerosol clearance studies may provide a valuable diagnostic adjunct.
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Acknowledgments
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The following is an abbreviated list of participants. (For a complete list of study participants, see reference 5.) From the National Heart, Lung and Blood Institute (Bethesda, Md): Hannah Peavy, MD (Project Officer), Anthony Kalica, PhD, Elaine Sloand, MD, George Sopko, MD, MPH, Margaret Wu, PhD. Chairman of the Steering Committee: Robert Mellins, MD. Clinical centers: from Baylor College of Medicine (Houston, Tex), William Shearer, MD, PhD (principal investigator), Peter Hiatt, MD, Warren Moore, MD, Linda Davis, RN, BSN, Chuck Mazak, BS, Ruth McConnell, RN, BSN, Debra Mooneyham, RN, Teresa Tonsberg, RN; from Children's Hospital and Harvard Medical School (Boston, Mass), Steven Lipshultz, MD (principal investigator), Andrew Colin, MD, Victor Lee, MD, Suzanne Steinbach, MD, S. Ted Treves, MD, Mary Ellen Wohl, MD, Janice Hunter, MS, RN; from Mount Sinai School of Medicine (New York, NY), Meyer Kattan, MD (principal investigator), Stephen Heaton, MD, Chun Kim, MD, Andrew Ting, MD, Diane Carp, MSN, RN, Dao Religioso, Mary Anne Worth, RN; from Presbyterian Hospital in the City of New York/Columbia University, Robert Mellins, MD (principal investigator), Philip Alderson, MD, Matthew Fleischman, MD, Anastossios Koumbourlis, MD, Scott Miller, MD, Kimberly Geromanos, RN, MS, CNS; from University of California at Los Angeles School of Medicine, Samuel Kaplan, MD (principal investigator), David Chen, MD, Meena Garg, MD, Carl Hoh, MD, John Miller, MD, Arnold Platzker, MD, Marlyn Woo, MD, Helene Cohen, RN, PNP, Lynn Fukushima, MSN, RN, Lucy Kunzman, RN, MS, Kevin Saiki, BS, Toni Ziolkowski, RN. From the clinical coordinating center at Case Western Reserve University (Cleveland, Ohio), Mark Schluchter, PhD (principal investigator), Amrik Shah, ScD, Richard Martin, MD, Atul Mehta, MD, Cindy Chen, MS, Kirk Easley, MS, Scott Husak, BS, Victoria Konig, ART, Lori Schnur, BS, Susan Sunkle, BA, CCRA. From the Policy, Data and Safety Monitoring Board: Henrique Rigatto, MD (Chairman), Edward B. Clark, MD, Robert B. Cotton, MD, Vijay V. Joshi, MD, Paul S. Levy, ScD, Norman S. Talner, MD, Patricia Taylor, PhD, Robert Tepper, MD, PhD, Janet Witts, PhD, Robert H. Yolken, MD, Peter E. Vink, MD.
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Footnotes
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For the Pediatric Pulmonary and Cardiovascular Complications (of Vertically Transmitted Human Immunodeficiency Virus) Study Group 
Supported by NHLBI contracts N01-HR-96037 through N01-HR-96043 and in part by NIH General Clinical Research Center grants RR-00188, RR-02172, RR-00533, RR-00071, RR-00645, RR-00865, RR-00043.
Address reprint requests to P.O.A.
Abbreviations: AIDS = acquired immunodeficiency syndrome
DTPA = diethyltriaminepentacetic acid
HIV = human immunodeficiency virus
Author contributions: Guarantor of integrity of entire study, P.O.A.; study concepts and design, P.O.A., R.B.M., H.H.P.; definition of intellectual content, P.O.A.; literature research, P.O.A.; clinical studies and data acquisition, P.O.A., D.C.P.C., M.J.F., C.K.H., C.K.K., V.W.L. J.H.M., W.H.M., S.T.T.; data analysis, A.S.; statistical analysis, A.S.; manuscript preparation, P.O.A., R.B.M., A.S.; manuscript editing and review, all authors.
Received December 30, 1997;
revision requested March 24, 1998; revision received July 29, 1998;
accepted October 7, 1998.
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References
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Abstract
Introduction
