Pediatric Radiology

H I V case b o o k

9 Springer-Verlag 1992 Pediatr Radiol (1992) 22:603-607

Bronchiectasis in children with lymphocytic interstitial pneumonia and acquired immune deficiency syndrome Plain film and CT observations J. K. Amorosa 1, R. W. Miller 1, L. Laraya-Cuasay 2, S. Gaur 2, R. Marone 2, L. Frenkel 2, J. L. Nosher 1 Department of Radiology, 2Department of Pediatrics, UMDNJ Robert Wood Johnson Medical School, New Brunswick, NJ, USA Received: 26 May 1992/Accepted: 22 June 1992

Abstract. In a r e v i e w of 77 H I V positive c h i l d r e n seen b e t w e e n 1981 a n d 1990, 32 w e r e d i a g n o s e d as h a v i n g l y m phocytic interstitial pneumonitis). F o u r of t h e L I P g r o u p d e v e l o p e d b r o n chiectasis, a finding n o t p r e v i o u s l y rep o r t e d . T h e p r e c i s e factors l e a d i n g to the b r o n c h i e c t a s i s a r e unclear. A l l p a tients h a d c h r o n i c a l l y c o n s o l i d a t e d lung with v o l u m e loss. A h i s t o r y of rec u r r e n t b a c t e r i a l s u p e r i n f e c t i o n was n o t n o t e d in a n y of t h e cases. W i t h m o r e cases of H I V p o s i t i v e c h i l d r e n living longer, b r o n c h i e c t a s i s , l o n g k n o w n to occur in p r i m a r y i m m u n o logic d i s o r d e r s , will p r o b a b l y b e m o r e frequently noted.

In r e v i e w i n g t h e i m a g i n g a n d clinical d a t a on p e d i a t r i c H I V p o s i t i v e cases, 4 w e r e f o u n d to h a v e b r o n c h i e c t a s i s . A l l 4 had prior diagnoses of LIP (lymphocytic i n t e r s t i t i a l p n e u m o n i t i s ) . W e reviewed our overall experience with lung d i s e a s e in H I V disease. W i t h i n c r e a s i n g l o n g e v i t y of p e d i a t ric H I V infection, r e c o g n i t i o n of this p r e v i o u s l y u n r e p o r t e d p r o c e s s will und o u b t e d l y b e m o r e f r e q u e n t l y enc o u n t e r e d . P l a i n film findings w e r e a u g m e n t e d b y CT, t h e l a t t e r m o s t c l e a r l y d e f i n i n g the e x t e n t of i n v o l v e ment. Correspondence to: Dr. J.K. Amorosa, De-

partment of Radiology, UMDNJ Robert Wood Johnson Medical School, One Robert Wood Johnson Place CN 19, New Brunswick, NJ 08903-0019, USA

Materials and methods 77 children had been seen at Robert Wood Johnson University Hospital between 1981 and 1990 with a diagnosis of HIV infection. We reviewed their presenting history, signs and symptoms, clinical course, laboratory and imaging data. 23/77 were asymptomatic (class P-1 by CD C criteria) and 54 were symptomatic (class P-2) [1]. 32 patients had been diagnosed as having LIP either by biopsy (15) or clinical course. All biopsies had been performed prior to 1986; since then, because of better clinical definition of LIR open lung biopsy has been less commonly performed. The lung tissue was stained and/or cultured for pneumocystis carinii pneumonia (PCP), acid fast bacillus (AFB), viruses (cytomegatovirus, herpes, etc.) fungi and bacteria. 16 patients had PCP. Interestingly, of the 32 diagnosed as LIE none had prior PCR Chest radiographswere available at diagnosis and at least annually thereafter. When bronchiectasis was suspected on conventional chest radiographs, further evaluation with CT was performed, using standard orhigh resolution (HRCT), initially on a Picker 600 and later a Picker 1200.

Results (including case histories) F o u r cases of b r o n c h i e c t a s i s w e r e n o t e d ; all h a d p r i o r L I R T h e case hist o r i e s of t h e s e 4 p a t i e n t s ( r e p r e s e n t i n g 4 cases o f b r o n c h i e c t a s i s o u t of a t o t a l of 32 L I P p a t i e n t s ) are s u m m a r i z e d below. Case 1. YS was 24 month old when HIV was diagnosed. She had presented with thrombocytopenia, hepatosplenomegaly, and a chest radiograph showing diffuse nodular opacities. LIP was confirmed on open lung biopsy. She went on to develop encephalopathy.

She had a chronic severe cough. Hypergammagtobulinemia was noted. She is till alive at age 9 years with chronic hypoxemia, tachypnea, and clubbing. By age 5 years the chest radiograph showed tubular densities in the mid and lower lung zones. These findings have persisted (Fig.l) Recent CT showed marked bronchiectasis (Fig. 2). Case 2. MB was diagnosed as HIV positive at age 15 months. He had hepatosplenomegaly and lymphadenopathy. Chest radiographs showed small rounded lung densities. Open lung biopsy showed LIR Since then, his maj or problems included failure to thrive (FTI'), encephalopathy, cardiomyopathy and renal failure. Hypergammaglobulinemia was noted. He was detected with a persistent right upper lobe process at age 3 years which was unchanged for the next several years (Fig. 3). High resolution CT (HRCT) confirmed bronchiectasis (Fig. 4). He died of respiratory failure at age 7 years. Case 3. MS was diagnosed as HIV positive at age 3 years. Shepresentedwith anemia,hepatosplenomegaly, and lymphadenopathy. Chest radiographs showed diffuse small lung opacities. The clinical diagnosis of LIP was confirmed by open lung biopsy. Hemophilus influenza was cultured from the lung tissue at the time of biopsy. She developed encephalopathy. She had failure to thrive and has hypergammaglobulinemia. Clubbing, hypoxia and tachypnea were noted. She died at age 7 years from massive pulmonary hemorrhage. From age 4 years, her plain chest radiograph (Fig. 5) and CT (Fig. 6) showed bronchiectasis within a persistent right middle lobe density. Case 4. TH was diagnosed as HIV positive at age 9 months when she presented with eczema, diaper dermatitis and thrombocytopenia. Chest radiographs showed diffuse small lung parenchymal densities. Open lung biopsy confirmed the diagnoses ofLIR Clubbingwas noted at age 7 years; at 9 years she is active in school. She has had frequent episodes of bronchitis. Plain chest radiographs have

rsity Hospital between 1981 i

nea, and

605 shown diffuse changes for several years. A persistent right middle lobe density was noted for the last two years (Fig.7). CT confirmed changes of bronchiectasis (Fig.8). Discussion

In looking at 77 HIV-infected children, it was clear that they fell into two groups. Sixteen had at least one episode of PCP while 32 had a diagnosis of LIE None of the LIP patients had PCR The LIP patients had clinical problems of clubbing, hypoxemia and tachypnea. Clinical bronchitis was present in some. The four cases of bronchiectasis associated with LIP survived for 9, 7, 7.1 and 9 years. All had initial diffuse small nodular patterns on chest radiographs. These changes were chronic, lasting for several years. In each case, a new pattern emerged over time. Case 1 developed mid and lower lung tubular densities. Case 2 developed right upper lobe consolidation, volume loss; the diffuse nodular changes persisted in all zones of both lungs. Case 3 developed right upper lobe consolidation, volume loss and dilated

Fig. 1. Patient 1. PA chest radiograph at age 9 years shows linear cylindrical opacities in lower lung zones Fig.2a, b. Patient1 aStandard resolution CT 8 mm thick slice of the LLL shows tubular bronchiectasis, b High resolution CT 2 mm thick slice at the same level shows more bronchial wall detail demonstrating extensive severe bronchiectasis Figo3, Patient2. Frontal plain radiograph at age 4 years shows a RUL consolidation with minimal volume loss and some tiny nodular lung opacities bilaterally Fig.4. CT at age 61/2 years shows mildly ectatic bronchi in the atelectatic portion of the RUL Fig,5, Patient3. PA chest radiograph at age 6 years shows RML opacity with suggestion of air bronchograms Fig,6, CT scan of the chest shows cystic bronchiectatic changes in the RML at age 3 years Fig.7. Frontal chest radiograph at age 7 years of patient 4 shows RML opacity and scattered nodular opacities Fig,8, a Patient4. At age 9 years standard resolution shows crowded markings in the RML. b Patient 4. High resolution CT demonstrates crowded mildly ectatic bronchi in the atelectatic RML

tubular structures. Case 4 developed a chronic right middle lobe consolidation/volume loss pattern. None of the patients had severe episodes of viral or bacterial pneumonia. Aspiration was not identified as a clinical problem. There was no use of mineral oil in any of the patients. Thus, the initial pattern of diffuse small densities often seen as typical of LIP was noted to change with development of lobe consolidation, volume loss and finally bronchiectasis. The pulmonary manifestations of pediatric H I V infection have been extensively discussed in the last decade [2.4]. LIP is noted in 30-40 % of pediatric H I V patients [5]. PCP is the most common pulmonary infection in children, while mycobacterial, viral and bacterial infections are also seen [6]. Bronchiectasis has been noted in the setting of altered host defense. It is well known in genetic disorders such as cystic fibrosis, ciliary dyskinesia, and alpha- 1-antitrypsin deficiency. Clearly infection, bacterial, viral and fungal can be implicated in its development. In the adult it has been noted to develop in areas of chronic volume loss with fibrosis and parenchymal destruction; in this setting, while distal bronchial structures are destroyed, the more proximal bronchi become dilated [9]. LIP itself is characterized by lymphocytic infiltration of lung parenchyma including focal pulmonary lymphoid hyperplasia (PLH) and diffuse infiltration of the alveolar septa (LIP). Neoplastic lymphoproliferative disorders have occurred. The overall spectrum of such lymphocytic abnormalities has been termed lymphoid associated disorders (LAD). Presumably, the infiltration of the lymphocytes into the mucosa and submucosa of the respiratory bronchioles leads to destruction, fibrosis, atelectasis and bronchial dilatation. When the lymphocytes infiltrate the mucosa of the bronchioles, the nodules occur at branching airways. This has been called bronchial associated lymphoid tissue (BALT) [10]. The atelectasis in these conditions may be due to LIP itself, unresolved pneumonias, or perhaps the direct effect of human immunodeficiency virus itself. It is not clear at present why this previously unreported process of bronchiectasis is just

now being observed. A clear-cut association with recurrent bacterial superinfection was absent in our cases. LIP presents with respiratory symptoms of cough, dyspnea and hypoxia. Chest radiographs commonly show bilateral diffuse nodular densities. Though mycobacterial infection and occasionally PCP can present in such a fashion, the LIP patients tend to be somewhat older at diagnosis than the PCP cases, and to have chronic pulmonary symptoms. The pathogenesis of LIP is unclear. It may represent a direct response to H I V infection though an association with EB virus has been suggested. Steroid therapy has a variable effect with some patients experiencing clear improvement. Intravenous gammaglobulin therapy has been used to restore functional gammaglobulin and is thought to aid in controlling LIR Despite the patients having hypergammaglobulinemia their gammaglobulin may not be functional and thus humoral immunity may not be normal. All four of our cases had chest radiographs suggestive of bronchiectasis. All four had persistent abnormalities in the same lobe over several years. All four had dilated tubular structures with CT confirmation (2 severe, 2 mild). We are uncertain of the significance of bronchiectasis in H I V positive children with LIR It is not clear whether the LIP itself causes the bronchiectasis or there are chronic abnormalities of secretions and clearance with resultant chronic atelectasis. The natural history of humoral immunodeficiency diseases such as Bruton's agammaglobulinemia commonly show bronchiectasis as the disease progresses. The occurrence ofbronchiectasis in pediatric HIV-LIP cases may become more important as longevity increases in these children. Awareness of this process and use of CT (including H R C T ) will presumably show more cases. Acknowledgement. The authors wish to thank

Marilyn Toth for computer assistance, Judith Buttenbaum for photographic assistance, Genevieve Cibelli for secretarial assistance, Marshall Barnhard for film copying, Tommy Ryan for film retrieval, JeffreyKaladas, RWJ IV and Paula Sharkey RWJ IV for reviewing the manuscript and Dr. Judith Johnson RWJ

606 90 for gathering data and Levina Aswani, Theresa Dougherty, Donna Earley, Julia Fulop andTheresa Wiggley,X-ray technologists.

References 1. Centers for Disease Control (1987) Revision of the CDC surveillance case definition for acquired immunodeficiency syndrome. MMWR [Suppl 15] 36:225-230 2. Rubinstein A, Morecki R, Silverman Bet al (1986) Pulmonary disease in children with acquired immune deficiency syn-

drome and AIDS-related complex. J Pediatr 108:498-503 3. Pahwa Savita (1988) Human immunodeficiency virus infection in children: nature of immunodeficiency, clinical spectrum and management. J Pediatr Infect Dis J 7:$61-$71 4. Scott GB (1988) Clinical manifestations of HIV infection in children. Pediatr Ann 17:365-369 5. Scott GB (1991) Special feature HIV infection in children: clinial features and management. J Acquired Immune Deficiency Syndromes 4:109-115 6. Scott GB, Hutto C, Makuch RW et al (1989) Survival in children with perina-

infection in addition to prior LIE A few have developed actual lymphomas. In some patients, cystic areas deThe disease complex known as lym- velop with problems of recurrent phocytic interstitial pneumonitis pneumothoraces. FinaIly, bronchiec(LIP) continues to attract attention. tasis has developed in some patients. As children live longer although H I V as noted in the ~ o r o s a paper. Its apinfected, the pattern of p u ~ o n a r y pearance a decade into the epidemic is most interesting. It does not seem, to involvement changes. Confluent consolidated areas of date, to reflect superimposed bactelung develop; some of the patients rial infection. To define all the factors prove to have either mycobacterium (atelectasis-related bronchiectasis. tuberculosis or avium intracellulare bacterialfungalsuperinfection.citiary

Editorial

Invited commentary R. Winchester Columbia College of Physicians and Surgeons, Division of Autoimmune and Molecular Diseases, Columbia-Presbyterian Medical Center, New York, NY 10032, USA Several generations ago Theobald Smith wrote cogently about the host parasite relationship, emphasizing the complex biologic interplay of the invasive and defense techniques that each employ. In H I V infection, the intricately orchestrated devastation of the host's immune system has been extensively documented, tempting one to conclude that, in this host parasite relationship, the human host can make no significant response. Yet, there is very considerable heterogeneity in the rate of progression of H I V

infection among various individuals. This suggests that differences in host responsiveness to H I V exist which perhaps may be determined by the presence of particular H L A alleles. Moreover, a small subset of adults and children, again denoted by other H L A alleles, develop a still incompletely defined syndrome of CD8 T cell lymphocytosis characterized by a variable infiltration of parotid, lung and other tissues by these cells. This has been designated the diffuse infiltrative lymphocytosis syndrome (DILS). Notably, still incomplete data indicates that the progression of H I V infection to immune deficiency in persons with DILS is greatly retarded. It appears that this subset of individuals has a markedly different host-parasite relationship with H I V that is characterized by a response to H I V a little more similar to that found in other chronic viral infection [1-3].

tally acquired human immunodeficiency virus type T infection. N Engl J Med 321: 1791-1796 7. Stanford W, Galvin JR (1988) The diagnosis of bronchiectasis. Clin Chest Med 9: 691-699 8. Barker AF, Bardana EJ, Jr (1988) Bronchiectasis: update of an orphan disease. Am Rev Respir Dis 137:969-978 9. Fraser R, Pare JAP (1988) Diagnosis of diseases of the chest, 3rd edn, vol 1. Saunders, Philadelphia, pp 491492 10. Bienenstock J, Johnston N, Perrey D (1973) Bronchial lymphoid tissue, T:Morphologic characteristics. Lab Invest 28: 686-693

Clearance problems) is to appreciate that it is probably multifactorial. It may be that the AIDS virus itself is capable of causing ectasia; certainly, sialectasia has been seen in immune problems of the parotid in the past. The adult HIV experience includes LIP as well. although it has been mainly noted on biopsies looking for PCP or TBC. The adults with LIP to date have not developed bronchiectasis. W.Berdon (Managing Editor)

The development of a distinctive response to HIV may itself exact a price. Amorosa et al. writing in this journal have investigated the distinctive subset of children who respond to H I V i n f e c t i o n - - not with the rapid development of opportunistic infection such as PCP but with an appearance of indolent and sometimes relentless progressive lymphocytic interstitial pneumonitis (LIP). Their central observation is that some patients in the LIP subset are developing frank bronchiectasis, previously unreported in LIE Increasingly it is recognized that many seemingly monolithic anatomic pathologic entities have diverse mechanisms of disease and correspondingly heterogeneous etiologies. Bronchiectasis is such a condition. One might simply conclude that the bronchiectasis in the cases of Amorosa, et al is due to recurrent infections