Organizing Diffuse Alveolar Damage Associated With Progressive Systemic Sclerosis

Case Report Organi zing Diffuse Alveolar Damage Associated With Progressive Systemic Sclerosis TRUDIE

E.

M UIR, M.D., HE RY D . TAZELAAR, M . D ., THOMAS

Diffuse a lveolar dama ge (DAD) is a re la tively non sp ecific pa tt ern of acute lung injur y th a t ca n be observed in a wide r ange of clin ica l ci rc u mstances. DAD has often been r ecognized in association with various co nnective tissue di seases ; ho wever, to ou r kn owled ge, it ha s not been previou sly r ep orted in the se tti ng of progr essi ve systemic sclerosis. H er ein we d escribe t wo pa t ients wit h es tablishe d di a gnoses of progressi ve sys te m ic scle r os is who had developmen t of th e ac ute r espirator y di stress syn d ro me. Ope n-l ung biopsy specimens fro m both pa tients showed a histologic patProgressi ve systemic sclerosis (PSS) is often classi fied into two cl inical ca tegories: the diffuse va ria nt of scleroderma (PSS- DS) and the more indol ent type of scleroderma, the CREST varia nt charac terize d by ca lcino sis cutis, Rayn aud 's phenome non, es ophage al dysrnotility, scle rodacty ly, a nd telangiectasia. PSS-DS is characterized by multisystem invo lveme nt, with vascu lar and connective tissue fibro sis and inflamma tion manifesting most prominently in the skin, gastrointest inal tract, lungs, and kidneys. Altho ugh inter stitial lung d isease (ILD) has been descri bed in pat ient s with both types of pSS ,I.2it is usu ally a late feature and is ge nerally not a major cause of morbidity or mortali ty. PSS-DS has a 7yea r mortal ity rate of 50 %,3and the mo st freq uent ca use of death are pulmon ary hypertension, heart failure, rena l fail ure, and bronchopneum oni a. Herein we des cri be two patients with PSS -DS who had developmen t of fulminant, fata l fLD , an unu sual complicat ion of PSS-DS.

REPORT OF CASES Case 1.- A previou sly healthy 53-year-o ld woma n sought med ica l attention because of swe lling of her right hand 16 months before ho spital adm issio n. Subseq uentl y, pai n and swe lling developed in her right ankle. Serol ogic tes t resu lts From the Division of Anatomic Pathology (T.E.M., H.D.T.. J.L.M.), Mayo Clinic Rochester. Rochester, Minnesota; and Department of Laboratory Medicine and Pathology (T.V.C.), Mayo Clinic Scou sdale, Scottsdale, Arizona. Address reprint requests 10 Dr. H. D. Tazelaar, Division of Anatomic Pathology, Mayo Clinic Rochester. 200 First Street SW, Rochester, M 55905. Mayo Clin Proc 1997;72:639-642

V. COLBY,

M . D., AND J EFFREY L. MYERS , M.D.

tern of DAD wit h no identifiable cause other than t he ir progressi ve syste m ic scle r os is. Ou r results sug ges t that DAD s ho uld be a d ded to th e list of pleu r opulmon ary co m plications of progressi ve syste mic scle r os is.

(Mayo CUn Proc 1997;72:639-642) AR DS = a cute r es p iratory di stress syn d ro me ; C REST = ca lci no s is c utis , Ra yn au d ' s ph en om e n on , eso p hagea l dysm otilit y, sclerodactyly, a nd telan giectas ia; DAD = diffuse alveolar da mag e; ILD = interstitial lun g disease; PSS = progr eso sive systemic scler osis; PSS· DS =di ffuse variant of PSS

for an tinuclear antibod ies, rheumato id factor , and Scl -70 antibody were neg ative. Ten months before admiss ion, she co mplained of skin light en ing, and a repeated ScI-70 antibody test was positive. PSS wa s diagnosed , and she was treated with 250 mg of penicillamine per day. Findings on ec hocardiog rap hy, pulmonary function stud ies, esophageal motili ty studies, and co mp lete blood ce ll counts we re no rmal 6 months before admissio n. Five months before adm ission, ho wever , her clinica l status began to dec line: her arthralgias became more severe, she had d yspn ea, an ec hocardi og ram showed a new pericardi al effusion with an enlarged heart , and pulmonary function tests revealed a restri ctive pat tern with decreased vital ca pacit y. Th e dosage of peni cillamine was increased , and cyclophosphamide and me thotrexate were added to the regimen . Th e arthralgias dim inished , but her skin tightness co ntinued to wo rsen. T wo months before ad mission, a chest roentgen ogr am showed bil ateral reticular infi ltrates. T wo wee ks before admi ssion, she had pancytopenia ; therefore, her medications were discontinued , and she rece ived transfu sions. On admiss ion to the hospita l, she had severe dyspn ea, and an interval increase was noted in the peric ardial effusio n. Pericardi ocen lesis and open -lun g biopsy were performe d. Routine cult ures of th is material for bact eri a, viruses , and fung i wer e nega tive. Antibiotic thera py was initiated; however, with in 4 days, she d ied of progressive resp iratory fail ure. Case 2. -A 70-year-o ld wo man with a 50- pack-year histo ry of smoking and a 2-ycar history of Raynaud 's phenom enon had development of system ic hypertension 7 months before admi ssion; she was treated with lisinopril. T wo 639

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PATHOLOGY Lung biopsy speci mens from both patients were similar and showed ac ute and organiz ing di ffu se alveolar dam age (DAD). Eosinophilic hyal ine membranes were present in both specimens and were most conspic uous along alveolar ducts and alveolar septa (Fig. 3). There was assoc iated alveolar septal thicken ing due to a combination of edema and inflammation , intra-alveolar ede ma, patchy hyperplasia of type II pneumocy tes, and early intra-alveolar and interstitial fibroblast proliferation. Special stains for organisms showe d no evidence of infection with bacteria. mycobacteria, fungi, or Pneumocystis carinii. Ne ither case had evidence of viral inclu sion s, chro nic fibros is, hon eycom b cha nge, or pulmonary hypertension. Immuno fluorescent stud ies in o ne patient (c ase 2) showed fibrin deposition predo minantly in the intra-alveolar spaces, but no imm unoglobulin, complement, or immune complex deposition was eviden t.

Fig. t (case 2). Chest roent genogram obtained JO days before admission, showing mild diffuse interstitial infiltrate throughout both lungs, with area of dense consolidation in apex of right upper lobe and slight amount of alveolar infiltrate in right lower lobe.

months before admission, she had increasing hortn ess of breath that was accompanied by a nonproductive cough. One month befor e admiss ion, she had hand, arm, back, and chest pain. Physical examination demonstrated clear lung field and acroscle rosis . Findings on chest roentgeno graph y were norm al. Laboratory studies yielded an increased leukocyte count (17 X 109/1...) and platelet count (772 X 109/1...), an increased creatinine level (3.0 mg/dL ) and erythrocyte sedimentation rate (58 mm in I hour ), and a positive antinuclear antibody screen ( I + homogeneous). PSS was diagnosed, and predn isone was initiated. Other medications at that time included desi pramine hydro chlo ride. lisinopril, levothyro xine sodium, nitroglycerin , and temazepam . Ten days before admission, repeated ches t roentgeno graph y showed a mild diffuse interstitial infiltrate throughout both lungs, with an area of dense consolidation in the apex of the right upper lobe and a slight amo unt of alveo lar infiltrate in the right lower lobe (Fig. I). On admiss ion, she had seve re dyspnea and tachypnea, with exte nsive, diffuse velcro rales in both lung fields. An arterial blood gas study revealed a partia l oxyge n tension of 4 1 torr , and ventilator therapy was initiated. A chest roentgenogram now showed diffuse bilateral interstitial and alveola r infiltrates (Fig. 2). She underwen t open-lung biopsy I day later. and routine cultures of this material for bacteria. viruses, and fungi were negative. She requested extubation on the fourth postoperative day and died of respiratory failure within 3 days .

DISCUSSION Our report of two patients with acute ILD associated with PSS and a histologic pattern of DAD sugges ts that DAD may be another manifestation of lung disease in patients with PSS. Unlike the other more common types of ILD (Table 1), however, DAD has a rapid. fulm inant deteriorating co urse. Pulmonary parenchymal abnormalities are commo n in PSS , even in the abse nce of classic cutaneo us involvement,'

Fig. 2 (case 2). Chest roentgenogram obtai ned at admissi on, demonstrating diffuse bilateral intersti tial and alveo lar infiltrates.

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Fig. 3. Photomicrograph of lung parenchyma. showing diffuse alveolar damage. Inset shows characteristic hyaline membranes (arrow). (Hematoxylin-eosin; original magnification: X160; inset, X400.)

and radiographic and high-resolution computed tomographic evidence of ILD has been reported in up to 90% of patients. 50S Symptomatic chronic pulmonary disease is less common and is typically associated with pleural thickening and fibro is. interstitial fibro sis. and honeycomb change that mainly affects the periphery of the lower lobes.>? In patients with the chronic variants of TLD, pulmonary function tests show eith er a restri ctive or an obstructive pattern.5.IO.12 In most reports, bronchoalveolar lavage has shown an increase in total leukocytes. with a high percentage of neutrophils in man y cases." Pulmonary hypertension occurs in most patients with scleroderma and can coe xist with other types of ILD as well as alv eolar hemorrhage. Pulmonary hypertension can progress independently of associ ated ILD I4 and tend s to be se vere in the CREST variant.i-" Patients with pulmonary hypertension usually have a chronic progressive course, but occa sionally they have a rapid clinical course with severe respiratory distress associated with pronounced right-sided heart failure and minimal interstitial disea se.v" Other less common patterns of lung disea se have also been reported in patients with scleroderma. These include bronchiolitis obliteran s organizing pneumonia, aspiration pneumonitis. and pleur al effusions," :" all of which usually manifest as chronic or subacute processes, Systemi c scle rosis complicated by alveolar hernorrhage-':" may manifest with a more fulminant course that is characterized by the acute onset of dyspnea, tachypnea , and fever. Chest roentgeno gram s demonstrate wide spread alveolar or alveolar-interstitial infiltrates that mim ic the appearance of the adult respiratory distress syndrome (ARDS). Lung biop sy speci-

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men s from patients with pulmonary hemorrhage have a com binati on of ac u te and organizin g hemorrh age and hemosiderosis. The histolo gic pattern of organizing DAD , as seen in the current cases, can be caused by various insults (Table 2)26.27 and is the most common histologic finding in patients with ARDS.6.26 Th e term "acute interstitial pneumonia" or "Hamma n-Rich syndrome" is sometimes used to describe the clinicopathologic syndrome of idiopathic ARDS .28 Clinically. such patients have acut e respiratory distress in conj unction with re fractory hypoxemia and pulmonar y edema, and usually they are dependent on a vent ilator. Th e radiographic appearance is well defin ed, although not specific . and progresses through three stages. In stage 1 (the first 12 to 24 hours), the rad iogram is clear unless the causativ e event is pulmonary in origin . Stage 2 corresponds to alveolar fillin g and shows patchy or diffuse interstitial opacification." In stage 3, the radiogram reveals a diffu se. bilateral ground-glass appearance , Becau se the etiologic factors of DAD are diverse, cau ses other than PSS must be considered in our patients. One patient (case I ) was takin g methotrexat e and penicillamine, both of whic h have well-known lun g toxicity" including DAD .30·31 This patient , however, had discontinued usc of these med ications by the time she sought medical treatment for respiratory distress; therefore, they are unlikely cau ses of her acute illness. She also had undergone transfu sion s, another known cause of ARDS.32 The tran sfusion s. howeve r, were I month before hospitalization. and the reports of tran sfusion-rel ated lung injury hav e all occurred within hours after the tran sfusion . Our other pati ent (case 2) received oxygen treatment for several days. another wellknown cause of DAD; how ever. her severe respiratory compromise occurred before the institution of oxygen therapy. Table I.-Clinical and Pat hologic Patt ern s of Lung Disease Associated With Prog ressive Systemic Sclerosis Clinical patterns Pleuritis Effusions Pleural thickening Airway disease Airflow obstruction Interstitial lung disease Acute interstitial pneumonia Alveolar hemorrhage Chronic interstitial pneumonia Bronchiolitis obliterans organizing pneumonia Vascular disease Pulmonary hypertension Vasculitis

Pathologic findings Fibrinous pleuritis Fibrous pteuritis Follicular bronchiolitis Diffuse alveolar damage Hemorrhage Usual interstitial pneumonia Bronchiolitis obliterans organizing pneumonia Intimal proliferation and medial thickening Vasculitis

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Table 2.- Com mon Ca uses of Ad ult Respiratory Distress Sy nd rome Aspiration Chemical inhalat ion Connective tissue diseases

Drugs

Idiopathic Infection Radiation therap y Shock Transfusion

9. 10. I \. 12. 13. 14. 15.

In both our patients, possible infec tious causes of DAD were excluded on the basis of negati ve cultures and special stains perform ed on lung biops y specimens. An immune complexmediated pathogenesis was ruled out based on negative reults of immunofluorescent studies. Therefore, the cause of lung injury in these patients seems most likely to be related to their underlying PSS. To our knowledge, DAD that is not assoc iated with infcction or immune complex deposition has not been previously reported in assoc iation with sclcrodenn a; however, it has been reported in conj unction with other connective tissue diseases, notably systemic lupus erythematosus.t-" mixed connective tissue disease with systemic lupus erythemato sus features, rheumatoid arthritis," and polym yositis-dermatomyositis." In our two patients, we believe that we ruled out treatment modal ities, drugs, and infec tion as causes of the ILD. In light of the clinical and patho logic evidence in the two cases presented herein, we think that PSS should be included with other connective tissue diseases as a cause of DAD and that acute ILD assoc iated with DAD should be added to the list of pulmonary diseases assoc iated with PSS.

16. 17. 18. 19. 20.

21. 22. 23.

24. 25. 26. 27.

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