Longitudinal, natural history study reveals the disease burden of idiopathic multicentric Castleman disease

Abstract

Idiopathic multicentric Castleman disease (iMCD) is a rare hematologic disorder with heterogeneous presentations ranging from moderate constitutional symptoms to life-threatening multiorgan system involvement. There are vastly different clinical subtypes, with some patients demonstrating thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin fibrosis/renal failure, and organomegaly (TAFRO) and others having milder/more moderate symptoms with potential for severe disease (not otherwise specified, NOS). Due to its rarity and heterogeneity, the natural history and long-term burden of iMCD are poorly understood. We investigated real-world medical data from ACCELERATE, a large natural history registry of patients with Castleman disease, to better characterize the long-term disease burden experienced by these patients. We found that iMCD-TAFRO patients face a significant hospitalization burden, requiring more time in the hospital than iMCDNOS patients during the year surrounding diagnosis (median [interquartile range]: 36 [18-61] days vs. 0 [0-4] days; P<0.001). In addition, we found life-sustaining interventions, such as mechanical ventilation (17%) and dialysis (27%), were required among iMCD patients, predominantly those with iMCD-TAFRO. iMCD-NOS patients, however, spent a significantly greater proportion of time following disease onset in a state of disease flare (median 52.3% vs. 18.9%; P=0.004). Lastly, we observed severe iMCD-related morbidities, such as acute renal failure, sepsis and pneumonia, among others, arising after iMCD diagnosis, impairing the patients' quality of life. These data demonstrate a substantial disease burden experienced by iMCD patients and emphasize the importance of ongoing research into iMCD to aid disease control.

Figure 1.

Patients with idiopathic multicentric Castleman disease demonstrate severe disease at diagnosis. (A) A large proportion of patients with idiopathic multicentric Castleman disease (iMCD) across all ages had severe disease. Notably, 95% of patients under the age of 30 years presented with severe disease at diagnosis. (B) Within the cohort of 102 iMCD patients, 87 (85.3%) had anemia and 81 (79.4%) had hypoalbuminemia at diagnosis. ^*Lower limit of normal for hemoglobin in males (12.5 g/dL). ^†Lower limit of normal for hemoglobin in females (11.5 g/dL). ^‡Lower limit of normal for albumin (3.5 g/dL). (C) A large majority of patients presented with clinical symptoms, which ranged from mild to severe. Patients with both clinical subtypes of iMCD (TAFRO and NOS) demonstrated clinical abnormalities. TAFRO: thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin fibrosis/renal failure, and organomegaly; NOS: not otherwise specified. these clinical signs, we found a substantial subset of NOS patients with the same severe clinical features. Among the 102 patients, 77 (76%) presented with severe disease at diagnosis, including 57 (93%) TAFRO patients and 20 (51%) NOS patients (Table 1). These data demonstrate that iMCD patients of any age and subtype can have severe and burdensome disease.

Figure 2.

Patients with idiopathic multicentric Castleman disease face a high burden of hospitalizations. (A) Patients with idiopathic multicentric Castleman disease (iMCD) are hospitalized a large proportion of time in the 6 months leading up to their diagnosis and the 6 months following diagnosis (year around diagnosis). The graph depicts each patient on the Y axis with the time hospitalized prior to diagnosis and the number of days hospitalized after diagnosis. Red indicates the time that iMCD patients with TAFRO (thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin fibrosis/renal failure, and organomegaly) spent in hospital, and blue indicates the time that patients with iMCD not otherwise specified (NOS) were hospitalized. In the 6 months prior to diagnosis, patients were hospitalized a mean (standard deviation [SD]) of 10.6 (17.5) days and a median (interquartile range [IQR]) of 5 (0-13.8) days, while in the year following diagnosis, patients were hospitalized a mean (SD) of 18.9 (28.2) days and a median (IQR) of 7.5 (0-25.0) days. (B) A sample of the USA population from the 2018 National Health Information Survey (NHIS), a proxy for the general population, spent significantly less time hospitalized in a 12-month period (median [IQR]: 0 [0-0], mean [SD]: 0.24 [1.3] days) than either TAFRO patients (median [IQR]: 35 [18-61], mean [SD]: 46.0 [42.0] days; P<2.2x10-) or NOS patients (median [IQR]: 0 [0-4], mean [SD]:4.9 [9.0] days; P=8.3x10-) spent hospitalized in the year around diagnosis. TAFRO patients were hospitalized significantly more days than NOS patients within the year of diagnosis (P=1.3x10-). ***P<0.001.

Figure 3.

Patients with idiopathic multicentric Castleman disease experience a range of organ system involvement, require various hospital interventions, and demonstrate ongoing flares. (A) Organ system involvement in idiopathic multicentric Castleman disease (iMCD) ranked from most frequently observed to least frequently observed. Over 97% of the iMCD cohort experienced some hematopoietic dysfunction. Notably, both patients with TAFRO (thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin fibrosis/renal failure, and organomegaly) and those with iMCD not otherwise specified (NOS) experienced significant organ system involvement and dysfunction. (B) The severity of organ dysfunction is reflected by the degree of healthcare intervention(s) required. Over one-quarter of patients (N=27 [26.5%]) required the use of a ventilator, and 17 (16.7%) patients required dialysis. Additionally, 47 (46.0%) patients required fluid removal (paracentesis), 42 (41.1%) patients received a red blood cell transfusion, and 22 (21.6%) patients received a platelet transfusion. (C) NOS patients spent a significantly greater proportion of time in flare from presentation until last known information (median [interquartile range]: 52.3% [21.0-99.6]) compared to TAFRO patients (18.9% [10.8-52.5], W=1673; P=0.004). (D) Each patient is represented by a vertical bar. The bar extends the length of follow-up from the start of the first flare. NOS patients are represented on the left, and TAFRO patients are represented on the right. The blue bars represent the proportion of time NOS patients spent in flare. The red bars represent the proportion of time TAFRO patients spent in flare. The designation ‘d’ indicates a deceased patient. RBC: red blood cells.

Figure 4.

Patients with idiopathic multicentric Castleman disease have numerous comorbid and morbid conditions contributing to the burden of the disease. (A) Prior to diagnosis, the most commonly diagnosed comorbidities among the full cohort of patients with idiopathic multicentric Castleman disease (iMCD) mirrored common comorbidities among the USA population and included hypertension (N=26, 25.5%), obesity (N=23, 22.5%), asthma (N=21, 20.6%), gastroesophageal reflux disease (N=14, 13.7%), and depression (N=11, 10.8%). (B) Following the diagnosis of iMCD, patients experienced an array of burdensome comorbidities and morbidities including acute renal failure (N=49, 48.0%), chronic kidney disease/chronic renal insufficiency (N=16, 15.7%) and iron deficiency anemia (N=11, 10.8%) among others. GERD: gastroesophageal reflux disease; ADHD: attention-deficit hyperactivity disorder; CKD/CRI: chronic kidney disease/chronic renal insufficiency; TMA: thrombotic microangiopathy; OSA: obstructive sleep apnea; NOS: not otherwise specified; TAFRO: thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin fibrosis/ renal failure, and organomegaly.

Figure 5.

Quality of life of patients with idiopathic multicentric Castleman disease is inversely correlated with degree of symptoms. There is a correlation between quality-of-life score and idiopathic multicentric Castleman disease (iMCD) symptom score. Lower quality of life correlates with higher iMCD symptom score and higher quality of life correlates with lower iMCD symptom score (R=-0.69, P<0.001). NOS: not otherwise specified; TAFRO: thrombocytopenia, anasarca, fever/elevated C-reactive protein, reticulin fibrosis/renal failure, and organomegaly.