Gambini C

Montella S

Parisi F

Pettinato G

Rossi GA

SANTAMARIA, FRANCESCA

Archivio della ricerca - Università degli studi di Napoli Federico II

57ITAL J PEDIATR 2002; 28: 57-60SummaryWe present the case of a child with idiopathic interstitial lung disease unresponsive to ste-roids, diagnosed by biopsy. Recurrent respiratory infections contraindicated more aggressi-ve immunosuppressive treatment. Physical growth was markedly unsatisfactory. Because ofthe progressive deterioration of lung function, and of the continuous need for oxygen ad-ministration, a heart/double-lung transplantation was performed. At present, 4 years afterthe procedure, the patient appears clinically stable, with normal spirometry parameters.RiassuntoDescriviamo il caso di un bambino con polmonite interstiziale idiopatica diagnosticatacon la biopsia polmonare e non responsiva al trattamento cortisonico. L’aggiunta di altraterapia immunosoppressiva era controindicata dalla elevata frequenza di infezioni respi-ratorie ricorrenti. L’accrescimento staturo-ponderale era marcatamente compromesso. Acausa del progressivo peggioramento clinico respiratorio e della continua necessità diossigeno abbiamo effettuato un trapianto cuore-polmone. Attualmente, a distanza di 4 anni,il paziente è in buone condizioni cliniche e la funzionalità respiratoria è nella norma.IntroductionThe term interstitial lung disease (ILD) encompasses a wide range of condi-tions in which the clinical symptoms primarily include dyspnea or breathles-sness on exertion and/or at rest, and cough. Main histological findings consistof the infiltration of inflammatory cells, associated with fibrotic changes cha-racterized by fibroblast proliferation and excessive collagen deposition 1.ILD in children represents a real challenge for physicians because of difficul-ties in making the diagnosis and because treatment is sometimes less than op-timal 2. Indeed, although most pediatric ILD are caused by infectious agentsand are characterized by a quite good outcome the cases reported are similarto adult idiopathic interstitial pneumonias, in whom the etiology is hard toidentify, the response to treatment sometimes poor, and worsening of lungfunction may lead to respiratory failure 3.We herein report the case of a child with ILD unresponsive to steroids in whomlung transplantation was performed with good results.Case reportA four year-old Caucasian boy, whose parents are first-degree cousins, was re-ferred to our unit with a 1-year history of cyanosis and dyspnea on exertion.The family history was negative for respiratory diseases. He was free of respi-Key wordsInterstitial lung disease • LungtransplantationParole chiavePolmonite interstiziale • TrapiantopolmonareSubmitted: August 8, 2001Accepted: September 10, 2001Correspondence:Dr. Francesca SantamariaDipartimento di PediatriaUniversità «Federico II»Via Pansini 580131 Napoli, ItalyTel. +39 81 7463495Fax +39 5451278E-mail: santamar@unina.itCASE REPORTCASO CLINICOA boy with idiopathic interstitial lung diseaseUn bambino con polmonite interstiziale idiopaticaS. MONTELLA, G.A. ROSSI, C. GAMBINI, G. PETTINATO, F. PARISI,F. SANTAMARIADipartimenti di Pediatria ed Anatomia Patologica, Università «Federico II», Napoli;Dipartimenti di Pediatria ed Anatomia Patologica, Istituto «G. Gaslini», Genova; Unità di Terapia Intensiva Cardiologica, Ospedale «Bambino Gesù», Romasee Editorial on page 9ratory symptoms, and physical growth had been sati-sfactory until age 3 years, when progressive shortness ofbreath on exertion, cyanosis and fatigability began. Hisparents had noted the development of clubbing of thefingers six months earlier. In the year prior to admissionin our unit he had experienced a few episodes of upperrespiratory tract infections with fever and cough.At presentation the examination revealed fine, cracklingrales audible over both lung fields. The patient had drycough. There was prominent clubbing and moderate tosevere labial and limb cyanosis. Room air resting bloodgases indicated an arterial oxygen tension (PaO2) of 48mm Hg, a carbon dioxide tension (PaCO2) of 36 mm Hg,a pH of 7,35, and an oxygen saturation (SaO2) of 70%.Cardiac evaluation excluded heart failure. However, theelectrocardiogram showed right ventricular hyper-trophy. B-mode and Doppler echocardiography showeddilatation of the right heart cavities and pulmonary ar-tery; a high speed tricuspid regurgitation was also evi-dent. Estimated pulmonary systolic pressure was 50 mmHg while breathing 21% FiO2, and dropped to 25 mmHgwhen breathing 100% oxygen.The chest x-ray and the high resolution computed tomo-graphy (HRCT) of the lung revealed bilateral interstitiallinear and reticular opacities with areas of ground glassappearance mostly at the base (Fig. 1A, B). Immunode-ficiency and malignancy were excluded. Exposure topets, metals or organic dusts, and atopy were excluded.Diagnostic tests for gastroesophageal reflux and swal-lowing disorders were negative. Cultures obtained bynasal wash, and infectious titers were negative. Connec-tive tissue diseases, including rheumatoid arthritis, sy-stemic lupus erythematosus, polymyosite and scleroder-ma were excluded. The sweat test was negative and thepatient had never received drugs associated with pulmo-nary toxicity. Gallium-67 scintiscan showed diffuse,mildly increased uptake in both lungs. Bronchoalveolarlavage (BAL) count showed 350 x 103 cells x mm-3 with30% macrophages, 1% lymphocytes, 38,5% neu-trophils, 30% eosinophils. No pathogens were identi-fied. The thoracoscopic lung biopsy demonstrateduniform intense to moderate fibrosis. Uniform thicke-ning of the alveolar wall due to expansion of the cellu-lar matrix, with large numbers of proliferating fibrobla-sts and dense deposits of collagen and elastin fibers we-re evident. Cells infiltrating the alveolar septa weremainly fibroblasts and monocytes. Hyperplasia of typeII pneumocytes covering the surface of most alveoli wasalso present (Fig. 2A, B).Continuous oxygen and oral prednisone (2 mg/kg/day)therapy were started. After 6 months of treatment, theGallium-67 scan and the HRCT of the chest appearedsubstantially unchanged. Room air blood gases analysisrevealed a PaO2 of 58 mmHg and a CO2 of 43 mmHg.The results of the physical examination and cardiac eva-luation were unchanged. Recurrent respiratory tract in-fections requiring antibiotic treatment occurred, con-traindicating treatment with immunosuppressive agents.Exercise tolerance was minimal and physical growthwas markedly unsatisfactory. A heart/double-lung tran-splantation was proposed and successfully performed.At present, 4 years after the procedure the patient ap-pears clinically stable. The spirometry is within normalvalues; the patient has returned to a fully active life.DiscussionWe report on a patient with idiopathic ILD unresponsi-ve to corticosteroid treatment in whom progressive pul-monary deterioration, complicated by severe failure tothrive and recurrent respiratory infections contraindica-ting more aggressive immunosuppressive drugs, led tothe decision of lung transplantation.Currently, pediatric ILD are being reported more fre-quently than in the past 1. For most patients, respiratorypathogens, mainly viruses, are the primary causativeagents and the episodes are self limited. However, a li-mited number of cases may present with progressive si-S. MONTELLA, G.A. ROSSI, C. GAMBINI ET AL.58Fig. 1. (A) Chest x-ray showing reticulonodular densities. (B)HRCT scan showing diffuse interstitial thickening of the intra-in-terlobular septa, diffuse reticulonodular densities, and a predo-minance of ground glass opacities at the lung bases.gns and symptoms and do not respond to oral steroids 3.More aggressive immunosuppressive agents may be ad-ministered, but conflicting results have been obtained inboth children and adults 2. A recent preliminary study ofadults treated with interferon gamma plus prednisolonehas demonstrated substantial improvement in the pa-tients who had had no response to steroids alone 4. Lungtransplantation may thus represent an alternative andsuccessful option.According to the Katzenstein classification, most idio-pathic ILD are rarely seen in children, with the only ex-ception of non specific pneumonitis (NSIP). NSIP is de-fined as a chronic form of ILD lacking both the hetero-geneity and the variegated pattern of usual pneumonitis(UIP), as well as the extensive accumulation of pigmen-ted alveolar macrophages that characterizes the desqua-mative pneumonia (DIP) 5. The pathologic criteria ofNSIP include interstitial inflammation and/or fibrosis,the proportion of which could vary over a spectrum ran-ging from pure chronic inflammatory cell infiltration tofibrosis without any interstitial component 5. The clini-cal features mainly include a subacute onset, the relati-ve lack of clubbing, a rather low mortality rate, good re-sponse to steroids and frequent clinical recovery 6. Ne-vertheless some cases may exhibit clinical and hystolo-gical features resembling idiopathic interstitial fibrosis,and these patients seem to be at greater risk of dyingthan those with cellular, non fibrotic lesions.Whether our patient would fit the Katzenstein model ofthe histological and clinical course of ILD is still open toquestion. Presenting symptoms, chest examination, lungimaging findings showing interstitial reticulonodular pat-tern prominent at the lung bases with ground-glass opa-cities, and finally the poor response to steroids with pro-gressive clinical deterioration make it difficult to distin-guish this case from UIP. The lung biopsy indicated a fi-brotic lung disease with type II cells hyperplasia and fi-broblast proliferation, which is very uniform; this wouldbe very atypical for UIP, in which the distribution of the-se changes is rather patchy. The histological patternlooks more like what was described by Katzenstein asNSIP type III, which is characterized by minimal in-flammation but extensive fibrosis 5. BAL findings in thiscase were also somewhat atypical, in that there was anextremely high eosinophil count. While eosinophilia inILD indicates poor prognosis 7, it usually does not reachthis level, but this still remains a possibility.A recent multicentre survey on pediatric ILD pointedout the difficulties in applying the classification ofadults ILD to children 8. In this study, in 61% of the ca-ses in whom the pathologists were unable to classify thehistological pattern, the term of «non classified fibrosis»was used; in the remaining 35% a clear histological de-finition of the disease as DIP or UIP or NSIP or LIP wasmade.Registry data from the International Society for Heartand Lung Transplantation demonstrates that ILD is thesecond most common indication for lung transplantation9. The successful outcome achieved in our patients afterthe lung transplant confirms that with increasing techni-cal refinements and experience lung and/or heart-lungtransplantation can be hopefully successful even in pe-diatric patients with ILD.In conclusions, our knowledge about ILD in childrenhas been limited in the past by the perception that it isuncommon at this age. The availability and applicabilityof diagnostic procedures in children has resulted in anincreased number of pediatric diagnoses 8. Finally, weconfirm that even in children unresponsive to oral glu-cocorticoids, progressive ILD represents an indicationfor lung transplantation.59IDIOPATHIC INTERSTITIAL LUNG DISEASEFig. 2. (A) Low magnification micrograph of the thoracoscopiclung biopsy specimen showing uniform thickening of the alveo-lar wall with large numbers of proliferating fibroblasts and den-se deposits of collagen and elastin fibers. Alveolar contentsshow a large number of macrophages. Hematoxylin and eosin;original magnification: x 125. (B) High magnification micrographof the same specimen showing fibrosis of alveolar septa with lar-ge numbers of proliferating fibroblasts. Note the type 2 alveolarcells hyperplasia and the macrophages into the alveolar space.Hematoxylin and eosin; original magnification: x 250.References1 Fan LL, Langston C. Chronic interstitial lung disease in children.Pediatr Pulmonol 1993;16:184-96.2 Fan LL, Kosinetz CA, Deterting RR, Brugman SM. Evaluation ofa diagnostic approach to pediatric interstitial lung disease. Pedia-trics 1998;101:82-5.3 Bokulic RE, Hilman BC. Interstitial lung disease in children. Pe-diatr Clin N Am 1994;41:543-67.4 Ziesche R, Hofbauer E, Wittmann K, Petkov V, Block LH. A pre-liminary study of long term treatment with interferon gamma-1band low dose prednisolone in patients with idiopathic pulmonaryfibrosis. N Engl J Med 1999;341:1264-9.5 Katzenstein AA, Myers JL. Idiopathic pulmonary fibrosis. Clinicalrelevance of pathologic classification. Am J Respir Crit Care Med1998;157:1301-15.6 Bjoraker JA, Ryu JH, Edwin MK, Meyers JL, Tazelaar HD, Sh-roeder DR, et al. Prognostic significance of histopatologic subsetsin idiopathic pulmonary fibrosis. Am J Resp Crit Care Med1998;157:199-203.7 Haslam PL, Turton CWG, Lukoszek A, Salsbury AJ, Dewar A,Collins JV, et al. Bronchoalveolar lavage fluid cell counts in cryp-togenic fibrosing alveolitis and their relation to therapy. Thorax1980;35:328-39.8 Barbato A, Panizzolo C, Cracco A, de Blic J, Dinwiddie R, ZachM. Interstitial lung disease in children: a multicentre survey ondiagnostic approach. Eur Respir J 2000;16:509-13.9 Hosenpud JD, Novick RJ, Bennet LE, Keck BM, Fiol B, Daily OP.The registry of the international society for heart and lung tran-splantation: thirteenth official report-1996. J Heart Lung Tran-splant 1996;15:655-74.S. MONTELLA, G.A. ROSSI, C. GAMBINI ET AL.60

A boy with idiopathic interstitial lung disease

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