Pathological Findings and Pulmonary Dysfunction After Acute Respiratory Distress Syndrome for 5 Years

□ CASE REPORT □

Pathological Findings and Pulmonary Dysfunction after Acute Respiratory Distress Syndrome for 5 Years

Chihiro Miwa 1, Shinichiro Koyama 1, Yasutaka Watanabe 1, Hiroyoshi Tsubochi 2, Shunsuke Endo 2, Mitsuhiro Nokubi 3 and Yoshinori Kawabata 4

Abstract

We report the pathological findings of the lung after acute respiratory distress syndrome (ARDS), and pulmonary function tests during five years of follow-up. A 39-year-old woman, treated for acute myelogenous leukemia, developed ARDS. She recovered from ARDS but suffered from pulmonary aspergillosis. Her aspergilloma was removed surgically. Her lung function tests and diffusing capacity of the lung for carbon monox-

ide (DLCO) improved but diffusion impairment remained five years after recovery. Pathological examination of the resected material showed sclerosis in lobular septa and scattered fibrosis in alveolar ducts except for the

aspergillosis. These fibrotic changes may be causally associated with her loss of DLCO.

Key words: acute respiratory distress syndrome, pulmonary function tests, diffusing capacity of the lungs, pathological findings in ARDS

(Inter Med 49: 1599-1604, 2010) (DOI: 10.2169/internalmedicine.49.3404)

and nail deformation due to chemotherapy. Other physical Introduction findings and blood examination were normal (Table 1). There were no abnormalities in bone marrow and cerebro- The acute respiratory distress syndrome (ARDS) is char- spinal fluid. The chest X-ray appeared normal (Fig. 1a). She acterized by acute lung damage, arterial hypoxemia, reduced had neutropenia in her peripheral blood from 8 to 30 days total thoracic compliance, and diffuse bilateral infiltrates on after chemotherapy. Twelve days after completion of chemo- chest radiograph due to increased-permeability pulmonary therapy she had a high fever and α-streptococcus was de- edema (1, 2). Survivors of ARDS are often found to have tected in her blood culture. The resulting septic shock and chronic pulmonary fibrosis, reduced pulmonary function, disseminated intravascular coagulation (DIC) were treated and diminished health-related quality of life (3-5). Further- by antibacterial drugs, γ-globulin, urinastatin, granulocyte more, there are few studies of pathological findings after colony-stimulating factor (G-CSF) and gabexate mesilate. ARDS. Here we report the pathological findings of the lung Sixteen days post chemotherapy her respiratory condition after ARDS, and this patient’s pulmonary function tests over worsened and her chest X-ray revealed bilateral diffuse pul- the five years after recovery. monary infiltrates with air-bronchograms (Fig. 1b). Arterial

oxygen pressure was 47.5 Torr with 15 L/min O2 flow via Case Report reservoir mask. LDH, AST, ALT and CRP increased to 327 IU/L 111 IU/L, 121 IU/L, and 21.7 mg/dL, respectively. She A 39-year-old woman was diagnosed with acute myeloge- was diagnosed with ARDS and intubated for mechanical nous leukemia (AML) in February, 2002. After induction ventilation. As part of multiple organ failure, her renal func- therapy for AML she received four courses of consolidation tion deteriorated and extracorporeal dialysis was begun. therapy at our hospital. On admission, she had loss of hair Subsequently, her temperature and arterial oxygenation im-

１Department of Pulmonary Medicine, Jichi Medical University Saitama Medical Center, Saitama, ２Department of Thoracic Surgery, Jichi Medi- cal University Saitama Medical Center, Saitama, ３Department of Pathology, Jichi Medical University Saitama Medical Center, Saitama and ４De- partment of Pathology, Saitama Cardiovascular and Respiratory Center, Kumagaya Received for publication January 18, 2010; Accepted for publication April 5, 2010 Correspondence to Dr. Chihiro Miwa, [email protected]

1599 Inter Med 49: 1599-1604, 2010 DOI: 10.2169/internalmedicine.49.3404 proved gradually, as did the chest X-ray. By 110 days post at this magnification (Fig. 3b). Microscopic sections of the chemotherapy she recovered sufficiently to become free of lung area away from aspergillosis, with stained with supplementary oxygen (Fig. 1c). elastica-Masson revealed scattered fibrosis in alveolar ducts On that same day (110 days) a fungus ball in a left lung and alveolar septa (Fig. 3c). cavity was recognized on her chest CT (Fig. 2). We checked After completion of treatment for AML, she was followed her sputum culture, and identified Aspergillus niger in a for five years. Over this period pulmonary function tests in- sputum sample and β-D-glucan was positive. A pulmonary cluding carbon monoxide diffusion capacity (DLCO)bysin- aspergilloma was diagnosed and treated with itraconazole. gle breath method and arterial blood gas analysis were per- Then, we added micafungin, because no improvement was formed according to standards recommended by the Ameri- shown on chest X-ray. However, her chest CT did not im- can Thoracic Society. Arterial blood gases returned to nor- prove and subsequently a new lesion appeared on the oppo- mal early in recovery from ARDS (Table 2). However, her site side of the lung. She therefore underwent excision of lung function tests showed a restrictive pattern of impair- the aspergilloma at 6 months after the onset of ARDS while ment at 2 years after recovery post ARDS. Thereafter her treatment of AML continued. pulmonary function tests gradually reached normal ranges

Pathological examination of the resected material showed (Table 3). Following recovery from ARDS, DLCO was less sclerosis in thickened lobular septa and the cuff of pulmo- than the normal range for 5 years (Table 3). As showing nary arteries, while slightly active bronchiolitis with intralu- corrected DLco,DLco for five years did not affect by her he- minal exudative material probably associated with recent as- moglobin (Hb). pergillosis was observed in the left lobule (Fig. 3a). There was also sclerosis in lobular septa and an arterial cuff. It ap- Discussion peared that air-space was mostly preserved in the left lobule The case-fatality rate of ARDS has decreased during the 1990s but still may exceed 30 percent (7, 8). The reasons Table 1. Laboratory Findings on Admission for the increased survival rate are unclear, but probably are

Hematology Biochemistry related to improved supportive care and ventilator strate- WBC 5130/μL TP 6g/dL gies (9). Low tidal volume ventilation improves survival in Nuetro 82% Alb 4.3g/dL patients with ARDS (10), although no correlation has been Lymph 11% T-bil 0.63mg/dL demonstrated between ventilatory strategies and long-term Mono 3% AST 16mU/mL Eosino 1% ALT 11mU/mL pulmonary function or health-related quality of life (5, 11). Baso 2% LDH 166mU/mL There is limited information regarding the pathological find- Blast 0% ALP 191IU/L ings of the lung and pulmonary function post ARDS. 4 RBC 323×10 /μL BUN 11mg/dL Many studies of patients with ARDS have focused on Hb 10.4g/dL Cr0.55mg/dL Ret 2.8% Na 143mmol/dL pulmonary morbidity and have shown that pulmonary func- Plt 30.3×104 /μL K 3.7mmol/dL tion most often returns to normal or is nearly normal by six Cl 105mmol/dL months to one year, with the exception of a persistent reduc- UA 4.5mg/dL tioninDLCO (12). However, Kian-Cheung et al (13) reported CRP <0.2mg/dL Patient’s blood examination was normal. that, one year after recovery from ARDS, persistent pulmonary function impairment was found in about one third of

a b c

Figure 1. a: Patient’s chest X ray on admission. b: Patient’s chest X ray showed bilateral diffuse pulmonary infiltrates with an air-bronchogram 16 days after chemotherapy. c: At 110 days after chemotherapy the patient had recovered completely and did not need supplementary oxygen.

1600 Inter Med 49: 1599-1604, 2010 DOI: 10.2169/internalmedicine.49.3404

Figure 2. At 110 days a fungus ball was recognized in the lung cavity on the chest CT. a b

Figure 3. a: Low power photo of a Hematoxylin and Eosin stained section. Sclerosis in thickened lobular septa (4 arrows), and cuffs around pulmonary arteries are noted (2 arrow heads). Slightly active bronchiolitis with intraluminal exudative material (circle), probably associated with recent aspergillosis, is observed in the lobule on the left. b: Low power figure of another Hematoxylin and Eosin stained section. There is also sclerosis in lobular septa (3 arrows) and arterial cuff (1 arrow head). It seems that air-space is mostly preserved in the lobules on the left (2 asterisks) at this magnification. c: Microscopic view of the square framed lung area in Fig. 3 b, after elastica-Mas- son staining. There is scattered fibrosis in alveolar ducts and alveolar septa.

1601 Inter Med 49: 1599-1604, 2010 DOI: 10.2169/internalmedicine.49.3404

Table 2. Arterial Blood Gas Analysis

Time from ARDS the onset of symptoms 5months 10months 5 years Inhalation O2 100% (intubated) room air room air room air pH 7.426 7.396 7.389 7.431 PaO2 (mmHg) 62.5 91.8 84.4 122.5

PaCO2 (mmHg) 57.8 46.6 46.7 37.3

HCO3- (mmol/L) 37.2 28 27.6 24.3

SaO2 (%) 94 97.7 97.3 99.3 Arterial blood gases returned to normal early in recovery from ARDS.

Table 3. Lung Function Tests

Time from ARDS 5 months 1.5 years 2 years 3 years 4 years 5 years VC (L) 1.83 1.96 1.92 2.17 2.15 2.28 %VC (%) 70.4 75.7 74.1 84.4 84 89.8 FEV1.0 (L) 1.74 1.8 1.81 1.96 1.96 1.92 FEV1.0% (%) 95.1 91.4 96.3 92.5 89.5 87.7 DLCO(mL/min/mmHg) 6.72 11.29 12.79 8.11 10.21 9.46 correctdDLCO 8.32 11.83 13.81 8.38 10.7 10.06 (mL/min/mmHg) (11.6) (13.7) (13.3) (13.9) (13.7) (13.5) (Hb(g/dL)) %DLCO (%) 50 74.5 85 52.6 66.7 59.8 DLCO/VA(mL/min/mmHg/L) 2.65 4.02 4.37 5.24 3.99 3.85 %DLCO/VA (%) 46.6 75.8 82.5 62.4 76.6 74.3 The restrictive pattern of impairment seen at 5 months after clinical recovery gradually improved through the next 4.5 years. Corrected DLCO: DLCO was corrected by Hb from a method of Dinakara et al (6).

patients. Schelling and colleagues (4) reported that even 5.5 the aspergillosis. At the same time, chest CT showed years after recovery from ARDS, the rates of obstructive and slightly ground glass shadows around the aspergilloma and restrictive pattern of impairment are still the same as the diffuse centrilobular ground glass shadows in all lung fields. rates after 1 year. Five years after the ARDS her chest CT was almost normal This may indicate that little improvement of lung function without evidence of an operational lung scar (Fig. 4). Her occurs after 1 year from ARDS (14). Similarly the present pulmonary functions were near normal except for some dif- case showed a restrictive pattern of impairment one year af- fusion impairment which still remained. ter clinical recovery, but this gradually improved through the Inger (16) pointed out that gradual remodeling or degrad- subsequent 4 years. Furthermore, DLCO gradually improved ing of the interstitial and alveolar fibrosis is the likely rea- during this period but diffusion impairment still remained. son why pulmonary function gradually improves in most Patients with ARDS tend to progress through three rela- survivors during the 6 to 12 months after onset of ARDS. tively discrete pathologic stages (15). The initial “exudative” The present case also demonstrates that pulmonary function stage, characterized by diffuse alveolar damage, gives way gradually improves over 12 to 30 months after onset of after the first week to a “proliferative” stage, characterized ARDS. Five years after the ARDS her chest CT was almost by resolution of pulmonary edema and by proliferation of normal, but we speculate that residual fibrotic changes in type II alveolar cells, squamous metaplasia, interstitial infil- the pulmonary alveolus wall are associated with reduced tration by myofibroblasts, and early deposition of collagen. DLCO. Some patients progress to a third “fibrotic” stage, characterized by obliteration of normal lung architecture, diffuse fi- Acknowledgement brosis, and cyst formation. However there have been few Authors thank Drs. Kouji Kikuchi and Mitsuo Nakayama, Sai- published studies of lung tissue following ARDS. tama Medical University, Saitama Medical Center, Department of The present patient underwent a surgical resection of the Thoracic Surgery, for surgical operation. aspergilloma six months after the onset of ARDS. Sections Authors also thank Dr. Jack Hildebrandt and Wayne Lamm, of the lung area removed from the aspergillosis were pre- University of Washington in Seattle, for editorial assistance. pared for microscopy with elastica-Masson staining. Patho- logical examination of the resected material showed slightly active bronchiolitis with intraluminal exudative material probably associated with recent aspergillosis in the left lobule. Scattered fibrosis appeared in alveolar ducts and alveolar septa, apparently related to the prior ARDS or possibly

1602 Inter Med 49: 1599-1604, 2010 DOI: 10.2169/internalmedicine.49.3404

Figure 4. Patient’s pre-operative chest CT showed slight ground glass shadows around aspergilloma. Five years after ARDS the chest CT appeared almost normal without any visible operational scar.

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