Pulmonary alveolar proteinosis (PAP) affecting transplanted lungs is not well recognized. Herein, we report two cases of PAP after lung transplantation (LTx). The first case was a 4-year-old boy with hereditary pulmonary fibrosis who underwent bilateral LTx and presented with respiratory distress on postoperative day (POD) 23. He was initially treated for acute rejection, died due to infection on POD 248, and was diagnosed with PAP at autopsy. The second case involved a 52-year-old man with idiopathic pulmonary fibrosis who underwent bilateral LTx. On POD 99, chest computed tomography revealed ground-glass opacities. Bronchoalveolar lavage and transbronchial biopsy led to a diagnosis of PAP. Follow-up with immunosuppression tapering resulted in clinical and radiological improvement. PAP after lung transplantation mimics common acute rejection; however, is potentially transient or resolved with tapering immunosuppression, as observed in the second case. Transplant physicians should be aware of this rare complication to avoid misconducting immunosuppressive management

Hattori, Noboru

Kawana, Shinichi

Matsubara, Kei

Miyoshi, Kentaroh

Okazaki, Mikio

Shimizu, Dai

Sugimoto, Seiichiro

Tanaka, Shin

Toyooka, Shinichi

Respirology Case Reports

English

Okayama University Scientific Achievement Repository

CA S E R E PO RTPulmonary alveolar proteinosis after lung transplantation:Two case reports and literature reviewShinichi Kawana1 | Kentaroh Miyoshi1 | Shin Tanaka1 | Seiichiro Sugimoto1 |Dai Shimizu1 | Kei Matsubara1 | Mikio Okazaki1 | Noboru Hattori2 |Shinichi Toyooka11Department of General Thoracic Surgery andOrgan Transplant Center, Okayama UniversityHospital, Okayama, Japan2Department of Molecular and Internal Medicine,Hiroshima University, Graduate School ofBiomedical and Health Sciences, Hiroshima, JapanCorrespondenceKentaroh Miyoshi, Department of ThoracicSurgery and Organ Transplant Center, OkayamaUniversity Hospital, 2-5-1 Shikata-cho, Kita-ku,Okayama 700-8558, Japan.Email: kmiyoshi@okayama-u.ac.jpFunding informationJapan Society for the Promotion of ScienceKAKENHI, Grant/Award Number: jp21k08882Associate Editor: Tracy LeongAbstractPulmonary alveolar proteinosis (PAP) affecting transplanted lungs is not wellrecognized. Herein, we report two cases of PAP after lung transplantation (LTx).The first case was a 4-year-old boy with hereditary pulmonary fibrosis whounderwent bilateral LTx and presented with respiratory distress on postoperativeday (POD) 23. He was initially treated for acute rejection, died due to infectionon POD 248, and was diagnosed with PAP at autopsy. The second case involveda 52-year-old man with idiopathic pulmonary fibrosis who underwentbilateral LTx. On POD 99, chest computed tomography revealed ground-glassopacities. Bronchoalveolar lavage and transbronchial biopsy led to a diagnosis ofPAP. Follow-up with immunosuppression tapering resulted in clinical and radio-logical improvement. PAP after lung transplantation mimics common acuterejection; however, is potentially transient or resolved with tapering immunosup-pression, as observed in the second case. Transplant physicians should beaware of this rare complication to avoid misconducting immunosuppressivemanagement.K E YWORD Sgraft dysfunction, immunosuppression, lung transplantation, pulmonary alveolar proteinosisINTRODUCTIONPulmonary alveolar proteinosis (PAP) is a rare diseasecaused by abnormal accumulation of surfactant in thealveolar space. Secondary PAP is a minor subtype with apoorer prognosis than common autoimmune PAP.1 It canreportedly complicate haematologic disorders, infections,and immunodeficiency. PAP after lung transplantation(LTx) is regarded as secondary PAP caused by alveolarmacrophage dysfunction owing to immunosuppressionand clinically and radiologically mimics acute rejection.2However, PAP is not well-recognized as a post-lung trans-plant complication. Herein, we report two cases of PAPafter LTx.CASE REPORTCase 1A 4-year-old boy with hereditary pulmonary fibrosisunderwent bilateral LTx and subsequent immunosuppres-sive management with tacrolimus, prednisolone, and myco-phenolate mofetil (MMF). The early post-transplant periodwas uncomplicated, with grade 1 primary graft dysfunction(PGD). On postoperative day (POD) 23, the patient com-plained of shortness of breath. Computed tomography(CT) revealed bilateral ground-glass opacities (GGO) andinterstitial infiltrates (Figure 1A). The serum KL-6 levelincreased to 1629 U/mL, whereas C-Reactive Protein (CRP)Received: 27 March 2023 Accepted: 29 April 2023DOI: 10.1002/rcr2.1160This is an open access article under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License, which permits use and distribution in any medium,provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.© 2023 The Authors. Respirology Case Reports published by John Wiley & Sons Australia, Ltd on behalf of The Asian Pacific Society of Respirology.Respirology Case Reports. 2023;11:e01160. wileyonlinelibrary.com/journal/rcr2 1 of 5https://doi.org/10.1002/rcr2.1160levels were not elevated. Acute cellular rejection wasclinically suspected because infection and heart failure werenot evident. A high-dose bolus steroid was repeatedlyadministered without clinical response. Eventually, thepatient underwent plasma exchange and thymoglobulintherapy for presumed antibody-mediated rejection causedby non-HLA antibodies. Despite these varied therapies, hisrespiratory condition progressively deteriorated without adefinite diagnosis and response to treatment. Five monthsafter transplantation, he required mechanical ventilation,which resulted in a recurrent pulmonary infection withPseudomonas aeruginosa and methicillin-resistant Staphylo-coccus aureus (Figure 1B). The serum KL-6 (Krebs von denLungen-6) level was over 5000 U/mL (normal range,0–500 U/mL) at the time; however, CRP was not elevated.The patient ultimately died of sepsis associated withcatheter-related bacterial infection and pneumonia on POD248. Autopsy of the transplanted lungs led to the diagnosisF I G U R E 1 Computed tomography (CT) scan in case 1 displaying bilateral ground-glass opacities (GGO) and interstitial infiltrates (A: postoperative day[POD] 23) being exacerbated after increasing the dose of immunosuppression (B: POD 96). Histology of a lung specimen at autopsy showing diffuse intra-alveolar eosinophilic materials (C: haematoxylin-eosin stain; original magnification, 200) stained by surfactant protein A (D; original magnification, 40),indicating evidence of pulmonary alveolar proteinosis.F I G U R E 2 Computed tomography (CT) scan in case 2 displaying broadened bilateral centrilobular ground-glass opacities (GGO) (A: postoperative day[POD] 138) that disappeared after reduction of immunosuppressants (B).2 of 5 KAWANA ET AL. 20513380, 2023, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/rcr2.1160 by Okayama University, Wiley Online Library on [01/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons Licenseof PAP, which was histologically characterized by intra-alveolar accumulation of surfactant phospholipids and apo-proteins (Figure 1C, D).Case 2A 52-year-old man with interstitial lung disease (ILD) under-went bilateral LTx and a standard immunosuppressive regimenof tacrolimus, prednisolone, and MMF. Although PGD wasdetermined to be grade 3, the subsequent early post-transplantperiod was uneventful. On POD 99, a routine chest CT scanshowed slight bilateral centrilobular GGO without clinicalsymptoms or an inflammatory response. The diagnostic trialfor steroid increase was ineffective. On POD 105, he com-plained of exertional dyspnoea and hypoxia with a broadenedGGO on follow-up chest CT (Figure 2A). The serum KL-6levels were elevated, whereas the inflammatory response wasnot. Bronchoalveolar lavage fluid (BALF) analysis and trans-bronchial biopsy revealed intra-alveolar eosinophilic materialsstained with periodic acid-Schiff (PAS). He was diagnosed withPAP and followed up by tapering immunosuppression in astandard manner. Thirty-two months after the onset of PAP,the lung opacities completely disappeared, and the patient wasdoing well without any respiratory discomfort (Figure 2B).DISCUSSIONThe aetiology of PAP is currently divided into three categories:autoimmune (90%), secondary (7%–10%), and congenital(<2%). In autoimmune PAP, neutralizing autoantibodies togranulocyte-macrophage colony-stimulating factor (GM-CSF)are central to pathogenesis.1 Secondary PAP is caused by dys-function or a reduced number of alveolar macrophages. Thepathology is related to diverse background complications,including haematological disorders, immunodeficiency disor-ders, infections, and toxic inhalation. Although LTx can causesecondary PAP, it is not well-recognized. However, the inci-dence of PAP after LTx remains unknown. In our institution,we have performed 215 LTx procedures since 1998, two ofwhich (1%) developed PAP. However, this incidence might havebeen underestimated because we did not routinely performBALF analysis and PAS staining for post-LTx surveillance.To date, 14 cases of PAP after LTx, including the presenttwo cases have been reported (Table 1).2–8 The median agewas 57.5 years (range, 4–69), and 71% were men. Thepatients received a single LTx (36%), bilateral LTx (57%), orheart-lung transplantation (7%) for interstitial pneumonia(IP) (71%), chronic obstructive pulmonary disease (14%), orothers (14%). The median time from LTx to the onset ofPAP was 99 days (range, 23 days to 5 years), while 64% ofpatients developed PAP within 6 months. Regarding thetiming of diagnosis, nine (64%) cases were not diagnosedbefore the initial intervention, and three (21%) of them werediagnosed at autopsy. After the diagnosis of PAP, immuno-suppression was adjusted in seven (50%) cases, GM-CSFwas used in three (21%), and alveolar lavage was performedin two (14%) cases. Regarding clinical outcomes, three(21%) patients recovered, one (7%) suffered persistent PAP,and eight (57%) died at a median time of 7 months (range,1–33 months) from PAP onset, mostly from infectious com-plications, accounting for seven (88%) of the total fatalities.The onset mechanisms of PAP after LTx have been pro-posed to be alveolar macrophage (AM) dysfunction due toimmunosuppressive therapy.2 ILD was significantly morecommon (72%) as a primary disease for LTx. Some studieshave suggested an association between immune cell dysfunc-tion, including AMs, and pulmonary fibrosis.9 Thus, recipi-ents who undergo LTx for IP may be more susceptible toalveolar AM dysfunction. Immunosuppression after LTxmay exacerbate the dysfunction of recipient-derived AMand lead to the development of PAP. The turnover rate ofTAB L E 2 Reported cases of PAP after LTx (outcomes, n = 12).Immunosuppressive managementNon-reductionn = 5Reductionn = 7 p-ValuePrognosis 0.081Improved 0 (0%) 4 (57%)Persisted or worsened 5 (100%) 3 (43%)Survival 0.576Alive 1 (20%) 3 (43%)Dead 4 (80%) 4 (57%)Follow-up period 3 months (1–33) 13 months (2–44) 0.255T A B L E 1 Reported cases of PAP after LTx (patients’background, n = 14).Age 57.5 (4–69)Male/female 10 (72%)/4 (28%)Primary diseaseIIPs/COPD/other 10 (72%)/2 (14%)/2 (14%)PAP onset 99 days (23 days–5 years)0–1 month 2 (14%)1–6 month 7 (50%)6–12 month 2 (14%)>12 month 2 (14%)DiagnosisBefore initial treatment 3 (21%)After initial treatment 6 (43%)Post-mortem 3 (21%)Immunosuppressive managementReduction 7 (50%)Non-reduction 5 (38%)NA 2 (12%)Abbreviations: COPD, chronic obstructive pulmonary disease; IIPs, idiopathicinterstitial pneumonias; LTx, lung transplantation; Not available, NA; PAP,pulmonary alveolar proteinosis.PULMONARY ALVEOLAR PROTEINOSIS AFTER LTx 3 of 5 20513380, 2023, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/rcr2.1160 by Okayama University, Wiley Online Library on [01/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons LicenseAMs from donor to recipient is reported to be 40–90% peryear, which is affected by lung damage.10 This implies thatPAP may occur when graft-resident AMs are replaced byrecipient-derived AMs. Among the five patients who devel-oped PAP after a single LTx in the retrieved literature, themajority (60%) exhibited unilaterally predominant develop-ment in the transplanted lung.2,3,6,7 This suggests that sometriggers derived from the transplanted lung, such as allore-jection or impaired lymphatic drainage, may coexist withAM dysfunction as a cause of PAP.The common clinical features of PAP are exertional dys-pnoea and cough with patchy GGO and interlobular septalthickening known as the “crazy paving” pattern on a chestCT scan. These clinical findings can also commonly appearas signs of AR in post-LTx settings. Once PAP develops inLTx recipients, it is difficult to distinguish it from othercauses of graft dysfunction, especially AR. Only three caseshad been diagnosed with PAP before the initial interventionin previous reports. A delay in reaching an accurate diagno-sis and intensifying immunosuppression with misdiagnosisof AR may lead to a worse prognosis. Among the 14 cases inthe retrieved literature, 12 with a description of prognoseswere subjected to subgroup analysis to compare outcomeswith or without immunosuppressive reduction (Table 2).While no patient in the non-reduction group did not dem-onstrate any improvement, 57% of patients in the reductiongroup showed improvement of PAP (p = 0.08). A similartrend was observed in survival. The poor prognosis of thenon-reduction group might have been caused by an exacer-bation of macrophage dysfunction due to intensified immu-nosuppression, which not only exacerbated PAP itself butalso increased vulnerability to infection. This could explainthe high percentage of infectious complications as the causeof death. We would note that this case literature review ofsmall-sized sample provides only a suggestion, and furtherresearch into future cases is necessary.PAP after LTx can be potentially transient or slowlyprogressive, as observed in the second case; therefore, weshould correctly distinguish PAP from AR, and may be betteroff tapering but not intensifying immunosuppression. Araiet al. reported that serum KL-6 was useful for the diagnosis ofautoimmune PAP. The cut-off value of 2050 U/mL serumKL-6 levels was able to differentiate autoimmune PAP fromother interstitial lung disease with a sensitivity of 75% and aspecificity of 78%.11 Lung opacity without an inflammatoryresponse and markedly elevated KL-6 levels are potentialsigns of PAP. Once PAP is suspected, PAS staining of BALFshould be considered to distinguish this rare pathology afterLTx from common rejection and infection.In conclusion, we have reported two cases of secondaryPAP in LTx recipients, with successful and unsuccessfulmanagement. Transplant physicians should be aware of thisrare but manageable complication of LTx.AUTHOR CONTRIBUTIONSConceptualization: Kentaroh Miyoshi; formal analysis:Shinichi Kawana, Kentaroh Miyoshi. Investigation: KentarohMiyoshi, Shin Tanaka, Seiichiro Sugimoto, Dai Shimizu,Mikio Okazaki, Noboru Hattori, Shinichi Toyooka. Writing-original draft: Shinichi Kawana, Kentaroh Miyoshi, ShinTanaka. All authors contributed to revisions of the manu-script, provided final approval for the final version to bepublished, and agreed to be accountable for all aspects ofthe work.ACKNOWLEDGMENTSThis report was presented at the international Society forHeart and Lung Transplantation, the 42nd Annual Meetingand Scientific Sessions, Boston MA, USA.FUNDING INFORMATIONThis study was supported by JSPS KAKENHI [grant numberjp21k08882] for data collection and publication.CONFLICT OF INTEREST STATEMENTNone declared.DATA AVAILABILITY STATEMENTThe data that support the findings of this study are avail-able on request from the corresponding author. The dataare not publicly available due to privacy or ethicalrestrictions.ETHICS STATEMENTThe authors declare that appropriate written informed con-sent was obtained for the publication of this manuscript andaccompanying images.ORCIDKentaroh Miyoshi https://orcid.org/0000-0003-1589-1216REFERENCES1. Trapnell BC, Whitsett JA, Nakata K. Pulmonary alveolar proteinosis.N Engl J Med. 2003;349:2527–39.2. Yousem SA. Alveolar lipoproteinosis in lung allograft recipients. HumPathol. 1997;28:1383–6.3. Gal AA, Bryan JA, Kanter KR, Lawrence EC. Cytopathology of pul-monary alveolar proteinosis complicating lung transplantation.J Heart Lung Transplant. 2004;23:135–8.4. Tokman S, Hahn MF, Abdelrazek H, Panchabhai TS, Patel VJ,Walia R, et al. Lung transplant recipient with pulmonary alveolar pro-teinosis. Case Rep Transplant. 2016;2016:4628354.5. Darley DR, Malouf MA, Glanville AR. A rare case of everolimus-induced pulmonary alveolar proteinosis. J Heart Lung Transplant.2016;35:147–8.6. Philippot Q, Cazes A, Borie R, Debray MP, Danel C, HurtadoNedelec M, et al. Secondary pulmonary alveolar proteinosis afterlung transplantation: a single-Centre series. Eur Respir J. 2017;49:1601369.7. Ikeda S, Sekine A, Baba T, Katano T, Yamakawa H, Oda T, et al. Sec-ondary pulmonary alveolar proteinosis predominant in the trans-planted lung in patients with idiopathic interstitial pneumonia: anautopsy case. J Thorac Dis. 2018;10:E351–4.8. Divithotawela C, Apte SH, Tan ME, De Silva TA, Chambers DC. Pul-monary alveolar proteinosis after lung transplantation. Respirol CaseRep. 2020;8:e00566.4 of 5 KAWANA ET AL. 20513380, 2023, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/rcr2.1160 by Okayama University, Wiley Online Library on [01/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License9. Parimon T, Hohmann MS, Yao C. Cellular senescence: pathogenicmechanisms in lung fibrosis. Int J Mol Sci. 2021;22:6214.10. Maus UA, Janzen S, Wall G, Srivastava M, Blackwell TS,Christman JW, et al. Resident alveolar macrophages arereplaced by recruited monocytes in response to endotoxin-induced lung inflammation. Am J Respir Cell Mol Biol. 2006;35:227–35.11. Arai T, Inoue Y, Sugimoto C, Inoue Y, Nakao K, Takeuchi N, et al.CYFRA 21-1 as a disease severity marker for autoimmune pulmonary.Alveolar proteinosis. Respirology. 2014;19:246–52.How to cite this article: Kawana S, Miyoshi K,Tanaka S, Sugimoto S, Shimizu D, Matsubara K, et al.Pulmonary alveolar proteinosis after lungtransplantation: Two case reports and literaturereview. Respirology Case Reports. 2023;11:e01160.https://doi.org/10.1002/rcr2.1160PULMONARY ALVEOLAR PROTEINOSIS AFTER LTx 5 of 5 20513380, 2023, 6, Downloaded from https://onlinelibrary.wiley.com/doi/10.1002/rcr2.1160 by Okayama University, Wiley Online Library on [01/06/2023]. See the Terms and Conditions (https://onlinelibrary.wiley.com/terms-and-conditions) on Wiley Online Library for rules of use; OA articles are governed by the applicable Creative Commons License

Pulmonary alveolar proteinosis after lung transplantation: Two case reports and literature review

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Pulmonary alveolar proteinosis after lung transplantation: Two case reports and literature review

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