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Hindawi Case Reports in Immunology Volume 2022, Article ID 2104270, 4 pages https://doi.org/10.1155/2022/2104270 Case Report Pulmonary Alveolar Proteinosis Refractory to Plasmapheresis and Rituximab despite GM-CSF Antibody Reduction Aysenur Keske, Eric M. Destrampe, Byron Barksdale, and William N. Rose Department of Pathology, University of Wisconsin Hospital, 600 Highland Ave, Madison, WI 53792, USA Correspondence should be addressed to William N. Rose; firstname.lastname@example.org Received 20 September 2021; Revised 5 January 2022; Accepted 19 January 2022; Published 30 January 2022 Academic Editor: Christian Drouet Copyright © 2022 Aysenur Keske et al. *is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. We share our experience of a patient with pulmonary alveolar proteinosis who was refractory to plasmapheresis and rituximab despite a signiﬁcant reduction in the oﬀending antibody. He presented with shortness of breath, fevers, chills, and sweats for 4 months. He was diagnosed with autoimmune PAP based on typical radiology ﬁndings, bronchoalveolar ﬂuid analysis, and elevated anti-GM-CSF levels. Given his limited improvement with whole lung lavage and inhaled GM-CSF therapy, he underwent two series of plasmapheresis. Series one was 5 procedures in 6 days, and series two was 5 procedures in 9 days followed by rituximab. *ese did not appear to provide any lasting clinical beneﬁt in the year after plasmapheresis despite a marked decrease in serum anti-GM-CSF levels. However, about a year after plasmapheresis, he went into remission and has not required any treatment. (BALF) autoantibody levels appear to correlate with markers 1. Introduction of disease severity (such as radiological involvement of lung, Pulmonary alveolar proteinosis (PAP) is a rare disorder that AaPO2, PaO2, and serum LDH levels) . is due to disrupted surfactant production or macrophage- Whole lung lavage (WLL) is often described as the mediated clearance that leads to alveolar surfactant accu- standard of care and commonly used for rapid symptom mulation and an impairment of gas exchange . *e disease relief within days for symptomatic patients. A very rough can present with various manifestations ranging from estimate of “the response rate” is 60% . In the case of exertional dyspnea to superimposed life-threatening op- refractory or worsening symptoms, inhaled GM-CSF ther- portunistic infections and hypoxic respiratory failure . apy can be used. Plasmapheresis and rituximab are rarely PAP is heterogeneous, as it can have multiple etiologies. used therapies, as only few case reports have examined the Primary PAP is subdivided into hereditary or autoimmune eﬀectiveness of these therapies. To add our experience to this (previously known as idiopathic or acquired) forms that are sparse literature, we present a case report of a patient with associated with mutations of genes regulating surfactant autoimmune PAP who did not show improvement following metabolism (such as CSF2RA) and autoantibodies against two series of plasmapheresis. GM-CSF, respectively . Hematologic disorders and envi- ronmental exposures (such as silica) may impair macrophage 2. Case Presentation function and cause secondary PAP [2, 3]. Autoimmune mechanisms account for more than 90% of the cases . *e patient is a 28-year-old male with a history of asthma Despite the known relationship between GM-CSF autoan- and smoking. He presented to an outside hospital with tibody-mediated impairments in macrophage function and progressive shortness of breath, fevers, chills, and sweats for surfactant accumulation in alveolar spaces, no correlation 4 months. A computed tomography (CT) scan demonstrated between circulating autoantibody levels and disease severity bilateral geographic distributions of ground glass opacities has been reported [4–6]. However, bronchoalveolar ﬂuid with interspersed interlobular septal thickening. 2 Case Reports in Immunology He described a productive cough with clear-to-white orthopnea, edema, or weight gain. His measured saturations phlegm. He took a short course of amoxicillin-clavulanate were in the 70 s on room air and mid-90 s on 3 L of O at the without improvement in his symptoms. His shortness of outside outpatient clinic. His CXR showed worsening bi- breath progressed signiﬁcantly after 4 months, and he also lateral opacities (more prominent on the left) when com- developed hemoptysis. He was admitted to an outside pared to before, concerning for exacerbation of his PAP. His hospital where his initial CT chest showed multifocal areas of arterial blood gas analysis showed the following values on 2 L ground glass opacity in the upper and lower lobes with O : PH � 7.45, PCO2 � 27, PO2 � 73, relative sparing of the periphery. BICARBONATE � 18.0, BASE EXCESS � −4.0, and O *e diﬀerential diagnosis at that time included pneu- SATURATION � 94.1. Of note, no posttreatment arterial mocystis pneumonia, eosinophilic pneumonia, and orga- blood gas was available. His ambulatory oximetry study nizing pneumonia, vasculitis, autoimmune diseases, and demonstrated a gradually increased oxygen requirement up hypersensitivity pneumonitis. No organic antigen exposure to a maximum of 5 L. was identiﬁed in his history. Infectious disease markers for Given the recurrent symptoms after WLL #2, he was respiratory viruses, HIV, mycobacteria, and fungi were admitted for WLL #3 as well as a series of 5 plasmapheresis negative. Autoimmune and inﬂammatory markers (in- procedures in 6 days. Each therapeutic plasma exchange cluding ESR, CRP, ANA, ANCA, RF, and complement (TPE) consisted of a 1-plasma volume exchange via cen- levels) were negative. trifugal apheresis with 5% albumin as the replacement ﬂuid. Bronchoscopy with BAL was performed and revealed a His measured anti-GM-CSF autoantibody level was 103 milky ﬂuid that was PAS positive. He was discharged for mcg/mL (normal<5.0) prior to the ﬁrst TPE. After the third outpatient follow-up. He reported hypoxia at home (satu- plasmapheresis procedure, his anti-GM-CSF level decreased rations usually around mid to lower 80 s) with any activity. to 17.6 mcg/mL, but the patient reported no signiﬁcant He was unable to tolerate PFT on his outpatient visit. His clinical improvement. SPO2 on room air was 88%, and he required 2 liters per He was started on inhaled GM-CSF at the conclusion of minute (LPM) to keep his SpO2 greater than 89%. Given his this series of 5 TPEs. Just prior to being discharged, his persistent symptoms, he was referred to our hospital for ambulatory oximetry study demonstrated a minimally in- initiation of WLL. creased oxygen requirement up to a maximum of 1 L. He was He reported a consistent cough with exertion and clear kept on nebulized GM-CSF and repeated WLLs every 3-4 phlegm during his initial evaluation at our hospital. He weeks due to refractory disease for a duration of about four denied sick contacts or recent travel. He was working at a months. foundry making silica sand into casts for the past 3 years (6 Four months after the ﬁrst TPE series, another TPE days a week and 10 hours a day). He did not report history/ series was tried. Despite treatment with WLLs in the in- symptoms of GERD. No family history of PAP was reported. tervening period, he did not see any lasting improvement. He did not take any medications other than as needed *us, TPE was attempted again because it was well tolerated ibuprofen. Of note, he had no history of statin use. He was an and has a relatively low side-eﬀect proﬁle. He received a active smoker with a 7 pack-year history. Occult hematologic second series of 5 TPEs in 9 days. He was also given rit- malignancy as a cause of secondary PAP was excluded by uximab (1000 mg IV) once after the last procedure. Un- ﬂow analysis. Given his high antibody levels, autoimmune fortunately, he reported no signiﬁcant clinical improvement PAP was favored but PAP secondary to silica exposure could after the second TPE series. not be excluded. For about one year after the second TPE series, he *e ﬁrst bilateral WLL was performed, and he was continued to require WLLs every 3-4 weeks despite con- successfully extubated following a brief course of mechanical tinuous inhaled GM-CSF treatment. At that point, he re- ventilation. He did not require O at rest, but did require up ported that he felt better. For 3 months, he continued the to 2 L of O with activity when he was discharged. He re- GM-CSF treatment but did not undergo any WLLs. Also, at ported initial improvement in his respiratory status that that point, he also stopped GM-CSF. About 3 months after lasted a couple of days. He had increasing exercise intol- stopping GM-CSF, another 6-minute walk test was per- erance, increasing production of purulent sputum, and formed. He did not require any supplemental oxygen either intermittent chills and sweats 5 days after the procedure. at rest or after walking about 1300 feet. *e most recent plan A repeat CT chest performed at an outside hospital again was to continue to hold both GM-CSF and WLL, as he is in remission. showed a “crazy-paving” pattern with areas of subpleural sparing. Slight temporal progression within the basilar segments of the right and left lower lobes were reported. He 3. Discussion required 2 L of oxygen at rest and 2–4 L on exertion with an SpO2 of 72% on room air. He underwent a repeat WLL 20 As of this writing, we were able to identify only four case days after the initial procedure. He was mobilized shortly reports that were published in English in which plasma- after the procedure and discharged on the following day. pheresis was used for the treatment of autoimmune PAP due Two weeks after the second WLL, he reported worsening to incomplete responses to WLL. *e ﬁrst case demonstrated dyspnea and hypoxemia for a few days. He also reported a marked reduction in serum antibody level (1 : 6400 to 1 : increasing production of purulent sputum and intermittent 400) and simultaneous clinical improvement following 10 chills and fevers. He denied any chest pain, hemoptysis, TPEs . *e authors concluded that circulating antibody Case Reports in Immunology 3 made after excluding other causes. His exposures cannot be levels are likely to correlate with disease activity and can be used to measure treatment response. ruled out as contributors, but they were deemed less likely due to the short durations. An association between silica However, no clinical improvement was reported in another patient who was treated with the same treatment exposure and autoimmunity has been reported . *us, it schedule despite a reduction in serum antibody level is possible that a persisting silica-mediate autoimmune (250 μg/mL to 156 μg/mL) . Only short-term improve- disease could be a factor in his initial poor response to ment was reported in a third patient who was treated with treatment. He left his job in the foundry approximately 6 bilateral WLLs followed by 5 TPEs in 2 weeks . months after initial diagnosis and cut down on his smoking. A case of ﬁve consecutive daily TPEs followed by rit- *ose interventions may contribute his clinical improve- ment which may also support the possible eﬀect of envi- uximab was also reported . A signiﬁcant reduction in anti-GM-CSF levels (24.8 to 2.7 μg/mL) and a relatively ronmental exposure on the development of autoimmune PAP. However, silica-mediated immunological alterations long-term symptomatic remission were achieved by this protocol. *is suggested a possible beneﬁt of a more intense are not well understood, and we do not have enough in- formation on this patient to come to a deﬁnitive conclusion. plasmapheresis regimen along with rituximab. However, a similar plasmapheresis protocol followed by rituximab did Additionally, treatment response in our case was mainly not provide a clear beneﬁt in our patient despite achieving a evaluated based on the patient’s subjective symptoms, pulse marked reduction in the oﬀending antibody level. oximeter readings as reported by the patient, and the more A marked decrease in serum antibody levels with a more objective PaO2 values that were measured during hospi- intense plasmapheresis protocol is an expected result given talization. A chest X-ray was usually obtained both on ad- the fact that TPE decreases IgG . In our patient, his mission and following WLL. A pulmonary function test (PFT) performed about 12 months after initial diagnosis and antibody level decreased from 103 mcg/mL just before the ﬁrst TPE to 17.6 mcg/mL between the third and fourth TPEs. 11 after the ﬁrst series of TPE at our hospital was generally within normal limits (FEV1: 3.61 L, FEV1%PRED: 84, FVC: When accounting for reequilibration, the antibody level between TPE 3 and 4 can be estimated to be about 65–80% of 4.33 L, FVC% PRED: 84, and FEV1/FVC: 0.83) except for DLCO (uncorrected for hemoglobin) which was very mildly the starting level . *is roughly corresponds to what was measured in our patient, as his antibody decreased by about reduced at 20.87 ml/min/mmHg (67% of predicted). He was 80% from pre-TPE 1 to post-TPE 3. unable to tolerate a pre-TPE PFT. LDH levels were not However, we speculate that the absence of clinical im- obtained. No other ambulatory oximetry study results or provement for our patient during the year after two series of other functional test results are available other than the ones TPE may suggest a weaker correlation between the circu- we have included. We speculate that more objective data lating antibody level and disease activity. Moreover, the could have provided additional information about the pa- tient’s status following plasmapheresis. However, these all timing of his remission long after TPE does not support a temporal relationship between TPE and clinical have costs and limitations, and the ultimate “test” (the patient’s self-reported well-being) consistently yielded dis- improvement. Interestingly, BALF autoantibody levels were not ob- appointing results. tained in any of the previous patients including our case, although previous studies reported conﬂicting results re- 4. Conclusions garding the correlation between serum antibody levels and disease activity. Serum antibody levels are required for We share our experience of a patient with refractory au- making a diagnosis of autoimmune PAP conﬁdently as well toimmune PAP who was treated with 2 series of plasma- as ruling out secondary PAP (along with additional clinical pheresis as well as rituximab but did not improve clinically data). We speculate that BALF antibody levels may correlate despite a marked reduction in serum anti-GM-CSF level. more strongly. *e case is unusual because of his poor response to therapy. Some discussion of the soundness of the diagnosis is While we can only speculate about why his response to warranted. *e diagnosis of autoimmune PAP is mainly treatment was so poor, we hope that sharing our experience based on BALF ﬁndings and serum GM-CSF autoantibody can contribute to a better understanding of autoimmune levels . Our patient was diagnosed with autoimmune PAP PAP and related conditions. *ere was a very long interval at an outside hospital where BALF results were consistent between antibody reduction and remission, as he went into with PAP and a high serum antibody level was also found. remission about a year after plasmapheresis. *is suggests *ese results were verbally reported to the clinical team at that the antibody reduction therapies were potentially not our institution. A serum antibody test was also ordered by the imputable cause of his remission. our clinical team and conﬁrmed the serologic diagnosis of autoimmune PAP prior to the ﬁrst TPE. Abbreviations At the time of diagnosis, the patient was working in a foundry where he had been exposed to silica and sand for 2.5 PAP: Pulmonary alveolar proteinosis years. He was an active smoker with a 7 pack-year smoking GM-CSF: Granulocyte-macrophage colony- history. stimulating factor Since GM-CSF autoantibody levels are not elevated in BAL(F): Bronchoalveolar lavage (ﬂuid) secondary PAP, the diagnosis of autoimmune PAP was AaPO2: Alveolar-arterial oxygen pressure diﬀerence 4 Case Reports in Immunology  M. Luisetti, G. Rodi, C. Perotti et al., “Plasmapheresis for PaO2: Partial pressure of oxygen treatment of pulmonary alveolar proteinosis,” European Re- SpO2: Oxygen saturation spiratory Journal, vol. 33, pp. 1220–1222, 2009. TPE: Total plasma exchange  H. Yu, X. Sun, Y. Wang, Z. J. Xu, and H. Huang, “Whole lung LDH: Lactate dehydrogenase lavage combined with Granulocyte-macrophage colony CT: Computed tomography stimulating factor inhalation for an adult case of refractory WLL: Whole lung lavage pulmonary alveolar proteinosis,” BMC Pulmonary Medicine, vol. 14, Article ID 87, 20014. L: Liter  B. Garber, J. Albores, T. Wang, and T. H. Neville, “Plasma- μg/mL: Microgram/milliliter pheresis protocol for refractory pulmonary alveolar protei- Ig G: Immunoglobulin G nosis,” Lung, vol. 193, no. 2, pp. 209–211, 2015. PFT: Pulmonary function test  M. E. Brecher, “Plasma exchange: why we do what we do,” FEV1 (% Forced expiratory volume (% predicted) Journal of Clinical Apheresis, vol. 17, no. 4, pp. 207–211, 2002. PRED):  S. Lee, H. Hayashi, H. Mastuzaki, N. Kumagai-Takei, and FVC (% Forced vital capacity (% predicted) T. Otsuki, “Silicosis and autoimmunity,” Current Opinion in PRED): Allergy and Clinical Immunology, vol. 17, no. 2, pp. 78–84, DLCO: Diﬀusing capacity for carbon monoxide ESR: Erythrocyte sedimentation rate CRP: C-reactive protein ANA: Antinuclear antibody ANCA: Antineutrophil autoantibody RF: Rheumatoid factor. Data Availability No data were used to support the ﬁndings of this study. Conflicts of Interest *e authors declare no conﬂicts of interest. References  T. Suzuki and B. C. 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Case Reports in Immunology – Hindawi Publishing Corporation
Published: Jan 30, 2022
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