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IDCases
IDCases
IDCases
2214-2509
Elsevier

S2214-2509(24)00141-0
10.1016/j.idcr.2024.e02065
e02065
Case Report
A true challenge: Disseminated tuberculosis with tuberculous meningitis in a patient with underlying chronic liver disease
Kalangi Harika harikakalangi1693@gmail.com
a⁎
Boadla Laura Rivera laura.riveraboadla@mountsinai.org
a
Perlman David C. david.perlman@mountsinai.org
b
Yancovitz Stanley R. stanley.yancovitz@mountsinai.org
b
George Vani vani.george@mountsinai.org
b
Salomon Nadim nadim.salomon@mountsinai.org
b
a Division of Infectious Diseases, Mount Sinai Morningside/West/Beth-Israel, 1111 Amsterdam Ave, New York, NY 10025, USA
b Division of Infectious Diseases, Mount Sinai Morningside/West/Beth-Israel, 10 Union Square East, Suite 2H, New York, NY 10003, USA
⁎ Correspondence to: 1299 Coporate Dr, Apt 1721, Westbury, NY 11590, USA. harikakalangi1693@gmail.com
22 8 2024
2024
22 8 2024
37 e020658 11 2023
11 8 2024
18 8 2024
© 2024 The Authors
2024
https://creativecommons.org/licenses/by-nc/4.0/ This is an open access article under the CC BY-NC license (http://creativecommons.org/licenses/by-nc/4.0/).
Tuberculous meningitis (TBM) is a potentially life-threatening form of tuberculosis (TB) that affects the central nervous system. Its management in patients with concomitant chronic liver disease (CLD) presents unique challenges due to altered drug metabolism with potentially impaired spinal fluid drug penetration and hepatotoxicity. The standard regimen for TBM includes isoniazid (INH) and rifampin (RIF), and Pyrazinamide (PZA) which are metabolized by the liver and may cause hepatotoxicity, which can exacerbate preexisting liver disease. Thus, careful consideration is required to balance therapeutic efficacy with potential drug-induced hepatotoxicity. Regular monitoring of liver function tests and clinical response is essential to minimize adverse effects and optimize treatment outcomes. Further research is needed to establish evidence-based guidelines for the tailored management of TBM in this vulnerable patient subset. Overall, the treatment of TBM in patients with severe liver disease should be individualized and closely monitored.

Keywords

CNS Tuberculosis
Chronic Liver Disease
Anti-Tuberculosis Therapy
Hepatotoxicity
Tuberculous Meningitis
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pmcIntroduction

Central nervous system TB (CNS- TB) accounts for a small proportion of TB cases globally. It manifests as subacute lymphocytic meningitis or neurological deficits caused by space-occupying tuberculomas and it can cause significant morbidity and mortality. TBM accounts for 70–80 % of all CNS- TB cases [1].

In the United States, TBM accounts for 1–5 % of reported TB cases and is more commonly seen in persons with compromised immune systems, such as those with HIV/AIDS, and in some immigrant populations. TBM often presents with insidious symptoms, including headaches, fever, neck stiffness, and altered mental status. Prompt diagnosis and treatment are critical, as delays can lead to irreversible brain damage. Diagnosing TBM requires a combination of clinical assessment, imaging, and cerebrospinal fluid (CSF) analysis [2].

The standard treatment regimen for TB is also the standard treatment of TBM and includes a combination of first line anti- tubercular treatment (ATT) drugs, such as INH, RIF, PZA, and ethambutol (EM) [5].

Severe CLD impairs the liver's ability to metabolize drugs efficiently, potentially leading to increased concentrations in the bloodstream and increased drug-related toxicities [6], [7]. Potentially hepatotoxic ATT drugs, particularly INH, RIF and PZA, are primarily metabolized in the liver. Thus, when TBM occurs in the setting of severe liver disease, such as in patients with cirrhosis, the administration of these agents must be used with caution, considering the balance between therapeutic efficacy and potential hepatotoxicity [8].

We describe an elderly female patient who had untreated latent TB infection (LTBI) and previous treatment for breast malignancy who was found to have disseminated TB (pulmonary, bone marrow, and TBM) together with liver failure. This case report examines the complexity of administering ATT to patients with liver failure and concurrent TBM and the considerations surrounding drug selection, dosing adjustments, and monitoring of liver function in this uniquely challenging patient population.

Case presentation

A 67-year-old female presented to the emergency department on 03/10/2023 with four days of subjective fevers, chills, dyspnea, and worsening nonproductive cough. She was born in Ecuador and came to New York in 1970s. Past medical history included untreated LTBI, cerebrovascular accident with residual left sided hemiparesis, COVID-19 disease in March 2020 with subsequent presumed sequelae of interstitial lung disease (ILD), and stage I right breast infiltrating ductal carcinoma. Breast carcinoma was diagnosed in 2021 and was treated with lumpectomy, chemotherapy, and radiation therapy followed by adjuvant trastuzumab emtansine (TDM-1) and anastrozole. TDM-1 was subsequently stopped after six months in November 2022 due to respiratory failure. Herceptin/perjeta was started in December 2022. The patient did not report smoking, alcohol, drug use, or sick contacts. She lived with her grandson. She used to work as a home health attendant.

In the emergency department the patient was alert, oriented, in mild respiratory distress, tachypneic using accessory respiratory muscles and requiring supplemental oxygen through high- flow nasal cannula. The blood pressure was 94/61 mm Hg, pulse 102 beats per minute, temperature 100.2 F, and respiration 28 breaths per minute and weighed 76.7 kg on admission. On physical examination, she appeared in distress, the neck was easily moveable without resistance. Lungs were noted to have crackles and wheezing on auscultation. Mild edema of the peripheral extremities was noted. Neurological examination revealed left sided mild weakness (at baseline).

Initial laboratory tests are depicted in Table 1.Table 1 Initial Laboratory results.

Table 1	Results	Reference values	
WBC	8 K/uL	4.5 −11 K/uL	
Hemoglobin	11.2 g/dL	11.7 - 15.0 g/dL	
Platelets	89 K/uL	150 - 450 K/uL	
BUN	19 md/dL	6 - 23 mg/dL	
Creatinine	0.69 mg/dL	0.50 - 1.10 mg/dL	
Sodium	130 mmol/L	135 −145 mmol/L	
Chloride	100 mmol/L	96 −106 mmol/L	
Magnesium	2.0 mg/dL	1.7 −2.0 mg/dL	
Albumin	2.2 g/dL	3.5 - 5.0 g/dL	
Total bilirubin	1.6 mg/dL	0.1 - 1.2 mg/dL	
Direct bilirubin	1.0 mg/dL	< 0.9 mg/dL	
ALP	121 U/L	38 - 126 U/L	
AST	57	< 36 U/L	
ALT	16	< 46 U/L	
INR	1.3	0.9 - 1.1	
HIV1 Ag, 2 Ab	Non- reactive	Non- reactive	
HBsAg	Non- reactive	Non- reactive	
Hep C Ab	Non- reactive	Non- reactive	
Ferritin	816 ng/mL	5 −204 ng/mL	
ESR	63 mm/hr	0 −24 mm/hr	
CRP	63 mg/L	< 5.1 mg/L	
WBC: white blood cells, BUN: blood urea nitrogen, ALT: Alanine aminotransferase, AST: Aspartate aminotransferase, ALP: Alkaline phosphatase, INR: International normalized ratio, HIV: Human immunodeficiency virus, HBsAg: Hepatitis B surface antigen. Hep C AB: Hepatitis C antibody with reflex to PCR, ESR: Erythrocyte sedimentation rate, CRP: C-reactive protein.

A chest radiograph showed diffuse reticular opacities interpreted as consistent with diffuse pulmonary fibrosis, with no focal consolidations. A computed tomography (CT) of the chest with contrast showed severely reduced lung volumes and thick fibrotic bands distorting the lung parenchyma interpreted as persistent moderate to severe upper to midlung predominant fibrosis, subpleural reticular densities and bronchiectasis in the peripheral aspects of the right middle lobe (Fig. 1).Fig. 1 : Computer tomography of the chest on admission showed severely reduced lung volumes and thick fibrotic bands and findings were interpreted as severe bilateral lung fibrosis and subpleural densities as marked by the yellow arrow.

Fig. 1

The patient was treated for presumptive bacterial pneumonia with cefepime, azithromycin and vancomycin. One dose of IV methylprednisolone 60 mg was administered, and the patient was started on oral prednisone 40 mg daily for a suspected flare of ILD which she received for just two days. Blood cultures, urine cultures, a nasal culture testing for methicillin resistant Staphylococcus aureus, and respiratory cultures were collected and showed no growth. SARS-CoV 2 nasopharyngeal PCR, respiratory viral pathogen panel testing, and urine legionella tests were all negative. The patient developed fever, confusion, tachycardia, hypoxia, and supraventricular tachycardia (SVT) on the fourth hospital day and underwent cardioversion and intubation. The patient completed 7 days of antibiotics and remained off antibiotics and was successfully extubated on hospital day 14. She remained afebrile during this period and remained off systemic steroids. During this time, her liver function tests were significant for elevated AST 130 U/L (reference range <36 U/L), ALT of 58 U/L (reference range <46 U/L), alkaline phosphatase of 164 U/L (reference range 38 - 126 U/L), total bilirubin of 2.4 mg/dL (reference range 0.1 - 1.2 mg/dL) and a direct bilirubin of 1.5 mg/dL (reference range <0.9 mg/dL).

On hospital day 16, she developed leukopenia with WBC of 2.0 K/uL and worsening thrombocytopenia of 27 K/Ul. The direct bilirubin increased from 3.1 g/dL to 3.8 K/uL (reference range <0.9 mg/dL). Epstein Barr Virus (EBV) serologies revealed prior infection, CMV DNA PCR was not detected. A consultation for infectious diseases was requested due to pancytopenia. A right upper quadrant ultrasound showed increased hepatic echogenicity. A CT scan of the abdomen and pelvis showed nodular liver contour, moderate ascites, heterogenous, splenomegaly and a normal biliary tree (Fig. 2).Fig. 2 : Computer tomography of the abdomen and pelvis showing splenomegaly marked by the yellow line (Axial View).

Fig. 2

She remained off systemic steroids during the remainder of hospitalization. On hospital day 22, the patient was noted to be febrile to 100.6 F and hypoxic requiring supplemental oxygen through a high-flow nasal cannula. A repeat CT chest now revealed increased groundglass opacities and new multifocal airspace consolidation. She received meropenem and vancomycin. Blood cultures, urine legionella antigen, and respiratory pathogen panel were all negative. The patient's mental state, clinical condition, and laboratory results did not improve despite the antibacterial treatment. A physical examination on hospital day 26, now revealed a rigid neck in flexion, extension, and rotation. She had symmetric corneal reflexes, no facial asymmetry, tongue was midline, but movement was minimal. A CT head now showed marked hydrocephalus, no obstructing mass lesion, and chronic microvascular ischemic changes (Fig. 3).Fig. 3 : Computer tomography of the head without contrast showing hydrocephalus.

Fig. 3

A lumbar puncture (LP) was performed on day 27 and the results are shown in Table 2. Cerebrospinal fluid (CSF) cryptococcal antigen, Gram stain, acid fast bacilli (AFB) stain, and CSF meningitis/encephalitis panel PCR were all negative. Serum cryptococcal antigen and urine histoplasma antigen were also negative. Due to her TB risk factors, markedly elevated CSF protein, hypoglycorrhachia (<5 mg/dL) and presence of hydrocephalus on CT scan, empirical anti-TB regimen for TBM was considered but was not immediately initiated in the setting of worsening liver tests (T.Bili of 3 mg/dL, reference range 0.1–1/2 mg/dL).Table 2 Cerebrospinal Fluid- Cell Count and Differentials of the first and second Lumbar Puncture. RBC: red blood cells, WBC: white blood cells.

Table 2	Units	Results of 1st LP	Results of 2nd LP	Reference values	
WBC, CSF	uL	695	1248	0 −5/uL	
RBC, CSF	uL	1890	1115	0 μL	
Neutrophils, CSF	%	74	89	-	
Lymphocytes, CSF	%	18	10	-	
Monocytoid, CSF	%	6	1	-	
Color, CSF		Yellow	Yellow		
Appearance, CSF		Hazy	Cloudy		
Proteins, CSF	mg/dL	369	490	15 −45 mg/dL	
Glucose, CSF	mg/dL	< 5	< 5	40 −70 mg/dL	
Adenosine deaminase, CSF	U/L		16	0 −9 U/L	

A second lumbar puncture three days later (on hospital day 30) again demonstrated neutrophilic pleocytosis, an elevated protein level, and marked hypoglycorrhachia. CSF adenosine deaminase was also elevated (Table 2).

The CSF gram stain from the second LP showed a few gram-positive bacilli (beaded) and many polymorphonuclear leukocytes (PMN). The CSF- AFB smear from the second LP also showed rare acid-fast bacilli. She was then started on ATT with RIF 600 mg daily, PZA 2500 mg daily, Linezolid 600 mg twice daily, Amikacin 15 mg/kg daily, Levofloxacin 750 mg daily and dexamethasone 0.4 mg/kg/daily on hospital day 31. A bone marrow biopsy of right iliac crest was performed on hospital day 29 revealing multiple necrotizing granulomas, however the AFB, GMS stains were negative (Fig. 4, Fig. 5).Fig. 4 : Bone marrow biopsy showing Multiple necrotizing granulomata (H&E; 10x).

Fig. 4

Fig. 5 : Giant cells in the granuloma (H&E; 40x).

Fig. 5

GeneXpert MTB/RIF PCR in CSF samples demonstrated MTB without evidence of rifampin resistance in either sample. CSF-AFB cultures from both the LP’s grew Mycobacterium tuberculosis complex. Two sputum AFB samples collected on hospital day 33 showed rare AFB on smear. The Gene Xpert MTB/RIF PCR on sputum samples confirmed detection of MTB complex DNA and rifampin resistance was not detected.

Given her liver morphology and elevated serum bilirubin, and lack of detected RIF resistance, to attempt to minimize use of potentially hepatotoxic agents while simultaneously capable of penetrating inflamed meninges, the initial regimen included levofloxacin, linezolid, PZA, RIF, amikacin, and adjunctive steroids 0.4 mg/kg daily. EMB was also added pending susceptibility testing as disseminated TB was suspected. Serum bilirubin rose from 3.8 mg/dl to 10/mg/dl (reference range 0.1 - 1.2 mg/dL) with two days of this ATT. PZA and RIF were discontinued.

She showed marked improvement in her mental status following ATT. On hospital day 44, i.e., about two weeks into ATT treatment, laboratory values also showed improvement and stabilization with WBC of 5.8 K/uL, total and direct bilirubin of 5.9 mg/dl and 4.7 mg/dl respectively. AST and ALT had normalized at this point. A decision was made to re-challenge with RIF 600 mg daily on this day. In 24 h post rechallenging, her total bilirubin again rose from 5.9 to 13 due to mg/dl and RIF was stopped due to progression of hepatic toxicity on day 2. There was no rash, respiratory distress, eosinophilia, or other signs of acute hypersensitivity reaction to RIF. She was continued on amikacin, ethambutol, levofloxacin, linezolid. Her course was subsequently complicated by acute hypoxic respiratory failure. Goals of care were discussed with the family, the patient was transitioned to palliative care, and she expired on hospital day 59.

Discussion

This case underscores the complexities of initiating ATT in patients with CLD. The patient presented with disseminated TB and CNS involvement due to reactivation of LTBI. This highlights the critical need for appropriate management of LTBI and the early identification of TBM to prevent progression and improve outcomes [1], [2].

The diagnosis of TBM remains challenging due to difficulties in the direct detection of M. tuberculosis bacilli in CSF and other specimens. Despite these challenges, empirical treatment should not be delayed when there is clinical suspicion, particularly with signs and symptoms of progressive illness. In our case, due to TB risk factors, markedly elevated CSF protein, and the presence of hydrocephalus on CT scan, empirical ATT for TBM was considered but not initially administered due to worsening liver function tests. A subsequent lumbar puncture led to the detection of acid-fast bacilli [2].

The management of TBM in patients with CLD is particularly challenging due to the potential hepatotoxicity of first-line anti-tuberculosis drugs, including INH, RIF, and PZA [3]. These drugs, although highly effective against TB, can exacerbate liver dysfunction, complicating their use in patients with pre-existing liver conditions. This discussion aims to provide a comprehensive view of the challenges, alternatives, and mitigation strategies for initiating ATT in CLD patients.

ATDs each carry their own risk of hepatotoxicity, and when used in combination, the cumulative effect on liver function may be significantly increased. INH, RIF, and PZA are known for their hepatotoxic potential. In patients with CLD, their use can lead to exacerbated liver damage, elevated transaminases, and in severe cases, acute liver failure. The risk of drug-induced liver injury (DILI) in patients with pre-existing liver disease increases significantly, complicating the management of TBM [4].

In patients with chronic liver disease, it is common to use fewer anti-tuberculosis agents than typically recommended, though the ideal number of drugs is not well-defined. Current guidelines from the American Thoracic Society (ATS) suggest reducing the use of hepatotoxic medications in those with advanced liver disease or significantly elevated ALT levels. When feasible, RIF should be included in the treatment regimen, while INH and PZA may be adjusted according to the severity of the liver condition and the overall clinical status [5].

Management strategies for tuberculosis in patients with preexisting liver disease can vary between healthcare centers, as there are no standardized guidelines specifically addressing the use of anti-tuberculosis therapy in these cases.

For patients with a CTP score below seven, indicating stable liver function, a regimen including two potentially hepatotoxic drugs, such as INH and RIF, is generally manageable. In cases with a CTP score between eight and ten, reflecting more advanced liver disease, treatment is adjusted to limit hepatotoxicity, with RIF preferred over INH due to its lower risk of liver damage. For patients with a CTP score of 11 or higher, indicating very advanced liver disease, hepatotoxic drugs are avoided. Instead, non-hepatotoxic alternatives like aminoglycosides (e.g., kanamycin, amikacin), fluoroquinolones, EMB, and streptomycin are used, often for 18–24 months, to effectively manage tuberculosis while minimizing liver strain [6].

In patients with underlying liver cirrhosis, treatment for TBM may initially include an aminoglycoside, a quinolone, and EMB. If additional medications are required, RIF can be introduced. If RIF cannot be used, INH may be considered as a substitute. PZA is generally best avoided in individuals with chronic liver disease due to its potential hepatotoxicity [6], [7].

Typically, the management of pulmonary and extrapulmonary tuberculosis is similar; however, cases involving central nervous system or skeletal tuberculosis may require extended antitubercular therapy. However, the hepatotoxicity of INH, RIF, and PZA necessitates careful monitoring and potential modification of the regimen and duration in patients with liver impairment [7]. Currently, there is a lack of consensus and data regarding the optimal duration of treatment for these conditions, especially when complicated by CLD.

Standard dosing of ATT may not be suitable for patients with CLD due to altered drug metabolism. Hepatic impairment can lead to increased drug levels and prolonged half-lives, heightening the risk of toxicity. Adjusting doses based on liver function is crucial but often lacks specific guidelines for optimal dosing in various stages of liver impairment.

Frequent monitoring of liver function is essential when initiating ATT in CLD patients. Elevated liver enzymes often necessitate adjustments to the drug regimen or discontinuation of hepatotoxic agents. This monitoring requires balancing the efficacy of the treatment with the risk of worsening liver function [8].

In our case, the initial use of RIF and PZA was associated with a significant worsening of liver function, necessitating their discontinuation. The patient was subsequently treated with second-line agents, which, although less effective for CNS penetration, proved necessary to manage the severe hepatotoxicity.

In cases where first-line agents are contraindicated or lead to unacceptable liver function deterioration, alternative regimens can be considered: Moxifloxacin and levofloxacin have good CNS penetration and are effective against TB. They are generally less hepatotoxic compared to INH and RIF and can be used in place of these agents when liver function is significantly impaired [9].

Linezolid and cycloserine are alternative drugs with good CNS penetration. They can be used in combination with other agents when first-line drugs are contraindicated. However, they come with their own side effect profiles and may require dose adjustments based on patient tolerance [10].

Regular monitoring of liver function tests (LFTs) is critical. In guidance for management of DILI, if serum transaminase concentrations are more than five times the upper limit normal (ULN), with or without symptoms, or more than three times the ULN with jaundice and/or hepatitis symptoms, potentially hepatotoxic agents should be reassessed, and the patient re-evaluated. If transaminase levels rise significantly, adjusting or discontinuing hepatotoxic drugs should be considered. In patients with worsening liver function, alternative regimens or a temporary cessation of therapy may be warranted. Re-challenge with hepatotoxic agent may be hazardous [3], [4], [6].

While there is guidance on the management of ATT in the setting of DILI, there are gaps in evidence regarding the initiation of ATT in patients with liver failure at the time of TB diagnosis [7].

Our case represented several challenges. Firstly, the challenge to diagnose TB meningitis. Her underlying liver diseases posed additional challenges, including unable to introduce highly efficacious drugs like INH, RIF and PZA due to their hepatotoxicity. The use of RIF and PZA was associated with a significant worsening in liver function leading to their discontinuation. The patient was subsequently treated with second line agents with clinical improvement. In our case, the reintroduction of rifampin was associated with worsening hyperbilirubinemia.

TBM continues to be a devastating complication of MTB and is associated with significant morbidity and mortality in the setting of diagnostic and treatment delays. In this case of disseminated MTB, isolated from pulmonary and cerebrospinal fluid with suspected bone marrow and liver infiltration, treating TBM with anti-TB agents characterized by increased brain permeability while minimizing hepatoxicity was challenging. While there are guidelines on management of DILI after initiating TB therapy based on cholestatic or hepatocellular dysfunction, the management is not clear-cut when initiating ATT, with pre-existing liver failure. Further data is needed regarding optimal therapy, monitoring, and the role of re-challenge in patients with pre-existing liver diseases. Further data is needed regarding mechanisms of DILI drug, and of genetic variation of enzymes involved in TB drug metabolism and transport. Engaging hepatologists and infectious disease specialists in the management of complex cases involving CLD and TB is crucial. A multidisciplinary approach ensures comprehensive care and optimal management of both liver disease and TB.

Conclusion

In conclusion, initiating ATT in patients with CLD presents significant challenges due to the potential for hepatotoxicity of first-line agents. Balancing the efficacy of treatment with the risk of exacerbating liver dysfunction requires a careful, individualized approach. Effective management involves assessing liver function before starting therapy, using alternative or second-line medications when necessary, and closely monitoring liver enzyme levels throughout the treatment course. Adjustments to dosing and the potential reintroduction of hepatotoxic drugs should be made cautiously. A multidisciplinary approach, incorporating input from hepatologists and infectious disease specialists, can enhance patient care and optimize treatment outcomes. Ongoing research is crucial to refine guidelines and improve management strategies for this complex patient population. Picture 1.Picture 1 : Chronological Overview of Clinical Events. HD: Hospital Day, ILD: Interstitial Lung diseases, SVT: Supraventricular Tachycardia, LFTs: Liver function tests, CT chest: Computed tomography of chest, CTAP: Computed tomography (CT) of the abdomen and pelvis, LP: Lumar Puncture, BM: Bone Marrow, ATT: anti-tuberculosis treatment, TBM: Tuberculous Meningitis, AFBs: Acid Fast bacilli, GMS: Grocott–Gömöri's methenamine silver stain, AST/ALT: Asparate aminotransferase/Alanine aminotransferase, RIF: Rifampin.

Picture 1

Ethical approval

NA.

Funding

This case report did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

CRediT authorship contribution statement

Harika Kalangi: Conceptualization, Data curation, Writing – original draft, Writing – review & editing. Laura Rivera Boadla: Conceptualization, Data curation, Writing – original draft, Writing – review & editing. David C. Perlman: Conceptualization, Supervision, Writing – review & editing. Stanley R. Yancovitz: Conceptualization, Supervision, Writing – review & editing. Vani George: Conceptualization, Data curation, Writing – review & editing. Nadim Salomon: Conceptualization, Supervision, Writing – review & editing.

Declaration of Competing Interest

The authors declare that they have no competing interests. This manuscript has not been published and is not under consideration for publication elsewhere. Additionally, all authors have approved this paper’s contents and agreed to the journal´s submission policies.

Data availability

Datasets used and analyzed during the current study are available from the corresponding author upon reasonable request.

Acknowledgment

Not applicable.

Authorship Contribution statement

All authors have read and approved the manuscript, and significantly contributed to this paper. HK, LR, SN, DP, VG: Conception and design, literature review, manuscript writing, and correction, final approval of the manuscript. SN, DP, SY: Revising manuscript critically for important intellectual content.
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