Clinical and laboratory predictors and prevalence of immune reconstitution inflammatory syndrome in patients with Whipple’s disease

Abstract

Objectives: Whipple’s disease (WD) is a rare and potentially fatal infectious disease caused by Tropheryma whipplei. It is characterized by a long prodromal phase that mimics a rheumatological disease, often leading to immunosuppressant treatment. Immune reconstitution inflammatory syndrome (IRIS) is currently the most important complication of WD, requiring prompt recognition and treatment as it can be fatal. However, epidemiological data on IRIS are scarce. We aimed to identify the clinical and laboratory predictors of IRIS at WD diagnosis and to evaluate whether the prevalence of IRIS has changed over time.

Methods: Forty-five patients with WD (mean age 52 ± 11 years; 10 females) were followed up between January 2000 and December 2021. Clinical and laboratory data at WD diagnosis were retrospectively collected and compared among patients who developed IRIS and those who did not.

Results: Erythrocyte sedimentation rate (ESR; 33.4 ± 11.8 mm/h vs 67.1 ± 26.3 mm/h,P < 0.01), platelet (PLT; 234 × 10⁹/L vs 363 × 10⁹/L,P < 0.01), and body mass index (22.0 ± 2.0 kg/m² vs 19.8 ± 3.0 kg/m²,P = 0.04) differed significantly between patients who subsequently developed IRIS and those who did not. ROC analysis identified ESR ≤46 mm/h (AUROC 0.88, 95% CI 0.72–1.00) and PLT ≤ 327 × 10⁹/L (AUROC 0.85, 95% CI 0.70–1.00) as optimal cut-off values to discriminate WD patients at a high risk of developing IRIS. Prevalence of IRIS remained stable (22.2%) over time.

Conclusions: Low ESR and PLT count at diagnosis help identify WD patients at high risk of developing IRIS. Instead, a greater inflammatory response suggests a lower risk of IRIS. Prevalence of IRIS did not change over two decades.

Keywords

chronic disease / chronic inflammation / immune reconstitution inflammatory syndrome / mortality / Whipple disease

References

[1] Li W,Fenollar F,Rolain JM, et al. Genotyping reveals a wide heterogeneity of Tropheryma whipplei. Microbiology (Reading). 2008; 154(Pt 2):521-527.

[2] Biagi F,Badulli C,Feurle GE, et al. Cytokine genetic profile in Whipple’s disease. Eur J Clin Microbiol Infect Dis. 2012; 31(11):3145-3150.

[3] Schöniger-Hekele M,Petermann D,Weber B,Müller C. Tropheryma whipplei in the environment: survey of sewage plant influxes and sewage plant workers. Appl Environ Microbiol. 2007; 73(6):2033-2035.

[4] Marth T,Moos V,Müller C,Biagi F,Schneider T. Tropheryma whipplei infection and Whipple’s disease. Lancet Infect Dis. 2016; 16(3): e13-e22.

[5] Mahnel R,Kalt A,Ring S,Stallmach A,Strober W,Marth T. Immunosuppressive therapy in Whipple’s disease patients is associated with the appearance of gastrointestinal manifestations. Am J Gastroenterol. 2005; 100(5):1167-1173.

[6] Trotta L,Biagi F,Di Stefano M,Corazza GR. Relationship between previous treatments and onset of symptoms in patients with Whipple’s disease. Intern Emerg Med. 2014; 9(2):161-164.

[7] Schiepatti A,Nicolardi ML,Marone P,Biagi F. Long-term morbidity and mortality in Whipple’s disease: a single-center experience over 20?years. Future Microbiol. 2020; 15:847-854.

[8] Feurle GE,Moos V,Schinnerling K, et al. The immune reconstitution inflammatory syndrome in Whipple disease: a cohort study. Ann Intern Med. 2010; 153(11):710-717.

[9] Lagier JC,Raoult D. Immune reconstitution inflammatory syndrome associated with bacterial infections. Expert Opin Drug Saf. 2014; 13(3):341-350.

[10] Moos V,Feurle GE,Schinnerling K, et al. Immunopathology of immune reconstitution inflammatory syndrome in Whipple’s disease. J Immunol. 2013; 190(5):2354-2361.

[11] Friebel J,Schinnerling K,Geelhaar-Karsch A,Allers K,Schneider T,Moos V. Intestinal barrier dysfunction mediates Whipple’s disease immune reconstitution inflammatory syndrome (IRIS). Immun Inflamm Dis. 2022; 10(5): e622.

[12] Biagi F,Trotta L,Di Stefano M, et al. Previous immunosuppressive therapy is a risk factor for immune reconstitution inflammatory syndrome in Whipple’s disease. Dig Liver Dis. 2012; 44(10):880-882.

[13] Morgenegg S,Dutly F,Altwegg M. Cloning and sequencing of a part of the heat shock protein 65 gene (hsp65) of “Tropheryma whippelii” and its use for detection of “T. whippelii” in clinical specimens by PCR. J Clin Microbiol. 2000; 38(6):2248-2253.

[14] Martinetti M,Biagi F,Badulli C, et al. The HLA alleles DRB1*13 and DQB1*06 are associated to Whipple’s disease. Gastroenterology. 2009; 136(7):2289-2294.

[15] Biagi F,Balduzzi D,Delvino P,Schiepatti A,Klersy C,Corazza GR. Prevalence of Whipple’s disease in north-western Italy. Eur J Clin Microbiol Infect Dis. 2015; 34(7):1347-1348.

[16] Hujoel IA,Johnson DH,Lebwohl B, et al. Tropheryma whipplei infection (Whipple disease) in the USA. Dig Dis Sci. 2019; 64(1):213-223.

[17] Ahmad AI,Wikholm C,Pothoulakis I, et al. Whipple’s disease review, prevalence, mortality, and characteristics in the United States: a cross-sectional national inpatient study. Medicine (Baltimore). 2022; 101(49): e32231.

RIGHTS & PERMISSIONS

2023 The Authors. Journal of Digestive Diseases published by Chinese Medical Association Shanghai Branch, Chinese Society of Gastroenterology, Renji Hospital Affiliated to Shanghai Jiaotong University School of Medicine and John Wiley & Sons Australia, Ltd.