A Case of Acute Fibrinous and Organizing Pneumonia During Early Postoperative Period After Lung Transplantation I.O. Alicia,*, E. Yekelera, A. Yazicioglua, S. Turana, Y. Tezer-Tekcea, F. Demiragb, and N. Karaoglanoglua a

Thoracic Surgery and Lung Transplantation Center, Turkiye Yuksek Ihtisas Education and Research Hospital, Ankara, Turkey; and Department of Pathology, Ataturk Chest Diseases and Thoracic Surgery Education and Research Hospital, Ankara, Turkey

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ABSTRACT Acute fibrinous and organizing pneumonia (AFOP) is a distinct histologic pattern usually classified under the term chronic lung allograft dysfunction. We present a 48-year-old female patient who experienced AFOP during the 2nd week of double lung transplantation for pulmonary Langerhans cell histiocytosis and secondary pulmonary hypertension. During the 8th day after transplantation, fever and neutrophilia developed together with bilateral consolidation. Infection markers were elevated. Despite coverage of a full antimicrobial spectrum, the situation progressed. The patient was diagnosed with AFOP with transbronchial biopsy. The infiltration resolved and the patient improved dramatically with the initiation of pulse corticosteroid treatment. AFOP should be suspected when there is a pulmonary consolidation after lung transplantation, even in the very early post-transplantation period. Several causes, such as alveolar damage and drug reactions, should be considered in the differential diagnosis.

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CUTE FIBRINOUS AND ORGANIZING PNEUMONIA (AFOP) is a distinct histologic pattern with intra-alveolar deposition of fibrin and is often related to organizing pneumonia [1]. Although it has been shown to be related to various conditions, there are few cases after lung transplantation. We present a case of AFOP which interestingly occurred during the very early postoperative period after lung transplantation. CASE PRESENTATION The patient was a 48-year-old woman who had undergone double lung transplantation surgery indicated for pulmonary Langerhans cell histiocytosis and secondary pulmonary arterial hypertension. The patient was discharged from the operation room to the intensive care unit with venoarterial extracorporeal membrane oxygenator (ECMO) which was constituted peripherally through the femoral vein and artery. T- and B-cell crossmatch was negative. She received alemtuzumab induction followed by initiation of intravenous tacrolimus and prednisolone. After a grade III primary graft dysfunction that was cleared on the 5th day, the ECMO was weaned on the 7th day after the operation. The day after (8th day), a fever (>39 C) developed together with neutrophilia and high C-reactive protein (CRP) and procalcitonin levels. The time line of the events is shown in Fig 1. Bilateral infiltrations on the chest roentgenogram grew in time. Computerized tomography of the thorax revealed an area of consolidation on the lower lobes bilaterally (Fig 2). Vascular and bronchial anastomoses and distal bronchial structures were patent. We immediately broadened the antibacterial spectrum and added systemic antifungal treatment because of the 0041-1345/15 http://dx.doi.org/10.1016/j.transproceed.2015.02.002

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history of ECMO and vaginal candidiasis. Bronchoalveolar lavage fluid (BALF) revealed marked neutrophilia without any remarkable microorganism. Oseltamivir was started but discontinued after 2 days because polymerase chain reaction (PCR) for community-acquired respiratory viruses in the BALF was found to be negative. Mycobacterial PCR and direct fluorescent antibody for Pneumocystis jirovecii were also negative. Despite full coverage of antiinfective therapy, the infiltration grew, the fever remained, and CRP and procalcitonin increased up to 38.8 mg/ dL and 76.7 ng/mL, respectively. The transbronchial biopsy from the right lower lobe revealed AFOP with a degree of interstitial thickening, intra-alveolar fibrin deposits, and organizing pneumonia. Eosinophilic infiltration and hyaline membranes were absent. There was no sign of acute rejection; ISLHT classification was A0Bx (Fig 3). Because of the severity of the clinical condition and the nature of the histologic diagnosis, we started a pulse corticosteroid therapy of 1 g/d intravenous methylprednisolone for 3 days followed by 1 mg/kg/d prednisolone. The infiltration resolved, fever declined, and other biomarkers decreased to normal levels within a week. Surveillance biopsy confirmed the healing process.

DISCUSSION

The early postoperative period after lung transplantation is usually a great challenge for a transplant team, with several *Address correspondence to Alici Io, Turkiye Yuksek Ihtisas Training and Research Hospital, Lung Transplantation Center, Kizilay Sok 06100 Sihhiye Ankara, Turkey. E-mail: ioalici@ hotmail.com ª 2015 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710

Transplantation Proceedings, 47, 836e840 (2015)

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Fig 1. Timeline giving the trends of several variables during the early postoperative period after lung transplantation. Note that the extracorporeal membrane oxygenator was weaned on the 7th day and the clinical deterioration started on the 8th day. Diagnostic work-up and empirical therapy were given from the 8th to the 12th days. On day 12, acute fibrinous and organizing pneumonia (AFOP) was diagnosed with the use of transbronchial biopsy and pulse corticosteroid (CS) therapy initiated; a rapid improvement has been achieved within a week. Abbreviations: CRP, C-reactive protein (mg/dL); PaO2, arterial oxygen partial pressure; PaO2/FiO2, ratio of arterial oxygen partial pressure to fractional inspired oxygen; Temp, body core temperature ( C); WBC, white blood cell count (103/mm).

distinct complications. Especially, infiltration on chest roentgenography after lung transplantation needs considerable attention to differential diagnostic work-up and immediate management strategies. Several conditions may lead to an opaque lung, but fortunately they usually occur in relatively specific time periods (Fig 4). For example, primary graft dysfunction usually starts within 48e72 hours whereas cytomegalovirus disease and acute rejection (AR) are the main actors during the 2nd week. On the other hand, ECMO may change the rules during the time it is active, because it may attenuate the signs of several conditions, such as hypervolemia, heart failure, and fever, which would become overt after weaning. Our case experienced severe primary graft dysfunction and required ECMO support during the 1st week. After the discontinuation of ECMOdand possibly the dose reduction in corticosteroidsdthe patient developed high fever and pulmonary infiltrations. We considered several conditions in the differential diagnosis. At first, primary graft dysfunction had

already healed and a hyperacute rejection was unlikely in that time period, so we excluded those. Computerized tomography revealed normal vascular anastomoses, so a possible vascular obstruction was also excluded. Bronchoscopic examination was normal, bronchi were patent, and there were no clots or mucus plugs. Patients easily develop pulmonary edema after the cessation of mechanical circulatory support of venoarterial ECMO. This condition usually presents with perihilar ground-glass opacities rather than bibasilar dense consolidations and responds well to diuretic treatment, which was not the case here. Besides, echocardiography revealed normal ventricular filling and systolic functions, and there were no signs of hypervolemia. So we excluded pulmonary edema. Fever was an important factor that may direct us to infections and infiltrative diseases. So we initially obtained all the required samples for bacterial, mycobacterial, fungal, and viral cultures and PCR analyses. Empirical antibacterial

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ALICI, YEKELER, YAZICIOGLU ET AL

Fig 2. Chest roentgenogram and corresponding computerized tomography slices at the time of transbronchial biopsy (A and B) and 2 weeks after (C and D) pulse corticosteroid treatment. Consolidation on the bases bilaterally and extensive ground-glass appearance together with interlobular septal thickening resembling pulmonary edema were seen at the time of the diagnosis (B). Later, a hematoma complicated at the right hemithorax (C and D).

spectrum was broadened: Systemic antifungal and antiviral agents were added. But none of the samples revealed a significant growth or presence of specific nucleic material. Infection had become unlikely but we retained the antiinfective spectrum. Besides, the occurrence time of fever was interesting: immediately after discontinuation of ECMO. As we know, ECMO has an extracorporeal circulatory conduit and a gas exchange membrane which results in significant heat loss. So it has a heating/cooling unit to maintain the body temperature to an adjusted constant. Probably the process had started earlier but ECMO removed excess heat

so fever became clinically apparent only after discontinuation of ECMO. This has clinical importance: A transplant team must be aware of this effect and know that the absence of fever during ECMO may not exclude infection or infiltrative diseases and eventually may lead to a delay in diagnosis of a potentially fatal condition. Acute rejections usually complicate the postoperative period after lung transplantation. The main disease in the differential diagnosis other than infection was acute rejection, considering the occurrence time, clinical signs, and radiologic features, so we obtained transbronchial biopsy.

Fig 3. Pathologic specimens of transbronchial biopsy. (A) Extensive young connective tissue in the interstitial space (hematoxylin-eosin, 200). (B) Interstitial accumulation of connective tissue and intra-alveolar fibrin deposits (trichrome, 400). (C) Intra-alveolar fibrin deposits (hematoxylin-eosin, 100).

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Fig 4. Preferential time of several complications with infiltrations on chest roentgenogram. Shaded area demarcates the period between clinical deterioration and significant improvement in the present case. Abbreviations: AR, acute rejection; CMV, cytomegalovirus; HAR, hyperacute rejection; PGD, primary graft dysfunction.

The histologic evaluation revealed no sign of perivascular and/or peribronchial lymphocytic infiltration. Lymphocytes and eosinophils were rare in the BALF, which was mainly neutrophilic. The diagnosis was AFOP with fibrin balls in alveoli. We gave the patient a pulse corticosteroid treatment and achieved a rapid clinical improvement. Nonetheless, we do not think the histologic diagnosis definitely excludes an acute rejection. Bronchoscopists usually obtain relatively small pieces of tissue compared with the extensive nature of the radiologic picture. When we consider this and the similar management of AFOP and AR, even though there was no histologic sign of apparent acute rejection, one can not prove that AFOP was the sole histologic pattern in this case; rather, it may be a different component or even a bystander process in an acute rejection episode. Even so, AFOP deserves special consideration in this paper. AFOP was first described by Beasley et al as a distinct histologic pattern showing intra-alveolar fibrin deposition and organizing pneumonia (OP) [2]. Well described patterns of diffuse alveolar damage (DAD), formerly so-called OP, eosinophilic pneumonia, acute pneumonia with abscess formation, granulomatous, and vasculitic involvement were reported as unacceptable features for the distinct definition. It was highlighted as a fibrinous variant of OP. They presented 17 cases with AFOP and reported that the associated conditions were collagen vascular diseases, history of exposure to various substances and possibly drugs, altered immune status (immunosuppressive medication, diabetes, and lymphoma), and infection. Subsequently, the condition was found in several situations, such as drug hypersensitivity reaction [3], collagen vascular diseases [4], and hypersensitivity pneumonitis [5], and caused by cigarette smoke [6] and even idiopathic [7]. There are few papers on occurrence of AFOP in lung transplantation patients. The most relevant paper, by Paraskeva et al [8], reported AFOP under the term chronic lung allograft dysfunction (CLAD) as a distinct entity besides

obliterative bronchiolitis and restrictive allograft syndrome. They analyzed 194 lung transplant candidates, of whom 87 patients (45%) developed CLAD during 8 years of follow-up and 22 patients were diagnosed with AFOP with intraalveolar loose fibrillary fibrin deposition. Secondly, Otto et al reported a case of AFOP related to H1N1 pneumonia after lung transplantation [9]. Parakseva et al reported that in their series, the median time to development of AFOP was 574 days [8]. The other case, reported by Otto et al, developed AFOP after H1N1 pneumonia during the 5th postoperative month. Our patient differs from those populations with very early presentation. AFOP is usually presented with patchy consolidations, diffuse centrilobular ground-glass opacities, and interlobular septal thickening [6,8,10]. Main symptoms are cough dyspnea and fever [11]. The symptoms and the signs in our patient were consistent with that situation. Our patient experienced severe alveolar damage by the meaning of graft dysfunction. Some authors raise a question about the relationships in the clinical spectrum of DAD, OP and AFOP and conclude that the difference may lie in the tissue sampling [1]. On the other hand, our patient received several kinds of drugs, such as immunosuppressants and antibiotics, during the course. The situation may easily be secondary to a drug reaction as to OP. There are also other signs favoring OP. We are very familiar with high fever and high levels of infection markers in OP. There was no sign of highly resistant microorganisms not covered by the antimicrobial spectrum. Also, the infiltration occurred after the graft dysfunction had already improved and presented as a consolidation, which is the main radiologic finding in OP. We may conclude that the AFOP may not be associated with a single etiology. It is reported that AFOP has 2 distinct types of course. Some patients present acutely with life-threatening findings and some present subacutely with prolonged disease course. These patterns also seem to differ in the disease

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progression, response to treatment, and prognosis. Some patients improve with antibiotics alone, but in general, less fulminant disease may resolve with 1 mg/kg/d prednisolone although relapses may occur, eg, owing to drug nonadherence [7]. In more severe cases, conventional doses of corticosteroids may fail [12]. Unfortunately, most of the patients with fulminant disease die of respiratory insufficiency and multiorgan failure despite pulse corticosteroid treatment and mechanical ventilation/extracorporeal life support [10]. Overall mortality is w50% but seems to be >90% in rapidly progressing fulminant disease [2,10]. Paraskeva et al reported that 21 of 22 patients (95%) with AFOP eventually died despite a 3-day course of methylprednisolone (5 mg/kg/d). The median (range) time to death was 101 (46e284) days [8]. Our patient experienced a lifethreatening rapidly progressing fulminant AFOP and fortunately responded to pulse corticosteroid treatment. Early transbronchial biopsy and rapid pathologic evaluation are crucial in lung transplantation patients. The situation resulted in delayed extubation and longer intensive care unit stay. Also, the patient experienced a degree of myopathy related to the high dose of corticosteroids and prolonged intensive care. Because mobilization is important, we rapidly lowered the corticosteroid dose, and after 12 months of follow-up there was still no sign of relapse or an (other) episode of acute rejection. The sings of proximal myopathy have already improved. CONCLUSION

Acute fibrinous and organizing pneumonia should be suspected and rapidly investigated when there is a pulmonary consolidation after lung transplantation even in the very early posttransplantation period. It mimics infection and acute rejection with clinical, radiologic, and biochemical features. Differential diagnosis usually relies on histologic evaluation. As in the present case, it may result in a life-threatening condition and yet is an underdiagnosed entity possibly due to a “tissue sampling issue.”

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REFERENCES [1] Travis WD, Costabel U, Hansell DM, King Jr TE, Lynch DA, Nicholson AG, et al. An official American Thoracic Society/European Respiratory Society Statement: update of the international multidisciplinary classification of the idiopathic interstitial pneumonias. Am J Respir Crit Care Med 2013;188:733e48. [2] Beasley MB, Franks TJ, Galvin JR, Gochuico B, Travis WD. Acute fibrinous and organizing pneumonia: a histologic pattern of lung injury and possible variant of diffuse alveolar damage. Arch Pathol Lab Med 2002;126:1064e70. [3] Yokogawa N, Alcid DV. Acute fibrinous and organizing pneumonia as a rare presentation of abacavir hypersensitivity reaction. AIDS 2007;21:2116e7. [4] Balduin R, Giacometti C, Saccarola L, Marulli G, Rea F, Bartoli M, et al. Acute fibrinous and organizing pneumonia in a patient with collagen vascular disease “stigma”. Sarcoidosis Vasc Diffuse Lung Dis 2007;24:78e80. [5] Hariri LP, Mino-Kenudson M, Shea B, Digumarthy S, Onozato M, Yagi Y, et al. Distinct histopathology of acute onset or abrupt exacerbation of hypersensitivity pneumonitis. Hum Pathol 2012;43:660e8. [6] Damas C, Morais A, Moura CS, Marques A. Acute fibrinous and organizing pneumonia. Rev Port Pneumol 2006;12:615e20. [7] Tzouvelekis A, Koutsopoulos A, Oikonomou A, Froudarakis M, Zarogoulidis P, Steiropoulos P, et al. Acute fibrinous and organising pneumonia: a case report and review of the literature. J Med Case Rep 2009;3:74e9. [8] Paraskeva M, McLean C, Ellis S, Bailey M, Wiliams T, Levvey B, et al. Acute fibrinoid organizing pneumonia after lung transplantation. Am J Respir Crit Care Med 2013;187:1360e8. [9] Otto C, Huzly D, Kemna L, Hüttel A, Benk C, Rieg S, et al. Acute fibrinous and organizin pneumonia associated with influenza H1N1 pneumonia after lung transplantation. BMC Pulm Med 2013;13:30e4. [10] Kang HJ, Choi SM, Jeong Y, Park JS, Lee SW, Yoon H, et al. Severe acute fibrinous and organizing pneumonia with acute respiratory distress syndrome. Tuberc Respir Dis 2011;71:368e72. [11] Lopez-Cuenca S, Morales-García S, Martín-Hita A, Frutos-Vivar F, Fernandez-Segoviano P, Esteban A. Severe acute respiratory failure secondary to acute fibrinous and organizing pneumonia requiring mechanical ventilation: a case report and literature review. Respir Care 2012;57:1337e41. [12] Lee SM, Park JJ, Sung SH, Kim Y, Lee KE, Mun YC, et al. Acute fibrinous and organizing pneumonia following hematopoietic stem cell transplantation. Korean J Intern Med 2009;24: 156e9.

A case of acute fibrinous and organizing pneumonia during early postoperative period after lung transplantation.

Acute fibrinous and organizing pneumonia (AFOP) is a distinct histologic pattern usually classified under the term chronic lung allograft dysfunction...
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