Overview

Castleman's Disease (CD) is a rare and complicated condition that affects the lymph nodes, which are integral to the body’s immune system. In some cases, the disease is limited to a single area and may not produce any symptoms. However, in other cases, particularly a type known as Multicentric Castleman Disease (MCD), it can lead to severe inflammation throughout the body. Three of the most common signs of MCD are fever, fatigue, and unexpected weight loss. These symptoms occur because the immune system becomes overactive, releasing an excess of chemical messengers called cytokines, which have widespread effects throughout the body. These symptoms often mimic infections, autoimmune diseases, or malignancies, making a timely diagnosis challenging. A thorough understanding of their pathophysiology and clinical relevance is crucial for both healthcare providers and researchers.

Types of Castleman Disease

Castleman's Disease is broadly categorised into two clinical types:

• Unicentric Castleman Disease (UCD) involves a single region of enlarged lymph nodes. Patients are often asymptomatic, and surgical excision typically results in a cure.
• Multicentric Castleman Disease (MCD) affects multiple lymph node regions and is associated with systemic inflammation, immune dysfunction, and multi-organ involvement. MCD can be further divided into:
  • HHV-associated MCD: Linked to human herpesvirus-8, frequently occurring in immunocompromised individuals such as those with HIV
  • Idiopathic MCD (iMCD): Occurs in HHV-8-negative individuals with no known cause

At the core of MCD pathology is the overproduction of interleukin-6 (IL-6), a pro-inflammatory cytokine that drives many systemic symptoms.¹

Fever: A marker of cytokine storm

Fever is a prominent symptom in MCD, which reflects excessive immune activation. Patients often experience persistent or intermittent fevers that do not respond to antibiotics and may resemble infectious or autoimmune diseases.

The fever is caused by high levels of IL-6, which acts on the hypothalamus to increase the body’s temperature set point. In addition, IL-6 stimulates the liver to produce acute-phase proteins such as C-reactive protein (CRP) and fibrinogen, both of which amplify the inflammatory response.²

The presence of unexplained fever, particularly when associated with swollen lymph nodes and elevated inflammatory markers in blood tests, should raise suspicion for MCD. These fevers often occur with night sweats, chills, and general malaise (feeling of being unwell), contributing to a reduced quality of life. In some cases, patients are extensively investigated for lymphoma (a type of cancer), tuberculosis, or heart infections, also known as endocarditis, before Castleman Disease is considered.⁶

Fatigue: A profound and persistent burden 

Fatigue in Castleman's Disease is not ordinary tiredness. Patients often describe it as overwhelming, unrelenting exhaustion that limits their ability to perform daily tasks. It significantly impacts both physical and mental well-being. Several factors drive fatigue:

• Inflammatory cytokines (e.g., IL-6, TNF-α) affect the central nervous system, disrupting neurotransmitter balance and sleep regulation
• Anaemia of chronic disease, common in MCD, decreases oxygen-carrying capacity. IL-6 stimulates hepcidin, a hormone that reduces iron availability and impairs red blood cell production³
• Metabolic dysregulation increases energy expenditure, even at rest

This symptom is particularly distressing because it often persists even where there are no obvious signs of active disease. Fatigue can also lead to cognitive dysfunction, sometimes referred to as “brain fog,” which makes concentration and decision-making difficult.

Management of fatigue requires addressing both its biological causes (inflammation and anaemia) and psychosocial impacts, including lack of physical fitness and depression.

Weight loss: The catabolic consequence

Unintentional weight loss is frequently reported in patients with MCD and may precede diagnosis by several months. It is often significant, involving loss of both fat and muscle tissue, and it happens because the body is in a highly active state of burning energy, driven by chronic inflammation.

IL-6 plays a central role by:

• Inducing lipolysis (the breakdown of fat) and muscle protein degradation, leading to loss of body mass
• Suppressing appetite by acting on hypothalamic centers in the brain that control hunger
• Increasing basal metabolic rate, which causes the body to burn more energy even at rest

Additionally, patients may experience early satiety (feeling full after eating a small amount), nausea, or even diarrhea, which further contributes to malnutrition. In advanced cases, severe cachexia (a serious form of body wasting) develops, reducing the body’s ability to respond to treatment and increasing vulnerability to infections.

Routine monitoring of body weight, BMI, and nutritional markers such as albumin and prealbumin is essential. Dietary support, and in some cases, enteral (tube feeding) or parenteral nutrition (feeding through a vein), may be needed to restore adequate energy balance.

Broader systemic involvement 

The triad of fever, fatigue, and weight loss rarely exists in isolation. In MCD, these symptoms often appear alongside: 

• Generalised lymphadenopathy (swollen lymph nodes throughout the body) and hepatosplenomegaly (enlarged liver and spleen)
• Edema (swelling) or pleural/pericardial effusions (fluid buildup around the lungs or the heart)
• Skin changes, such as cherry angiomas (small red spots) or violaceous rashes (purple-coloured skin patches)
• Peripheral neuropathy (nerve problems causing numbness or weakness), particularly in CD variants such as POEMS syndrome (charactersied by Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal plasma cell disorder, and skin changes)⁷

Systemic inflammation affects multiple organs and pathways, creating a vicious cycle in which immune dysregulation exacerbates catabolism (body tissue breakdown), anemia, and tissue injury¹.

Diagnosis: Piecing the puzzle

Due to the nonspecific nature of its symptoms, Castleman’s Disease is frequently misdiagnosed. Many patients undergo extensive evaluations for infections, autoimmune conditions, or cancers before arriving at the correct diagnosis.

Diagnosis workup typically includes:

• Blood tests: Checking for high levels of ESR and CRP (markers of inflammation), raised IL-6, low red blood cells (anemia), high platelet count (thrombocytosis), and low protein levels (hypoalbuminemia)
• Imaging: Using CT scans or PET-CT scans to look for swollen lymph nodes and enlarged organs
• Lymph node biopsy: Taking a sample of a lymph node to look under a microscope, where doctors look for specific features like atrophic germinal centers, follicular dendritic cell expansion, and increased blood vessels (vascularity)
• Virology screening: Testing to see if the disease is linked to the HHV-8 virus, which helps distinguish virus-related MCD from cases with no known cause (idiopathic MCD)

A comprehensive approach involving both clinical findings and pathological confirmation is essential to avoid delay and ensure appropriate treatment.⁴

Treatment and symptom relief

Treatment of CD varies depending on the subtype.

For Unicentric CD, surgical excision of the affected node is usually curative, and systemic symptoms resolve post-operatively.

In Multicentric CD, the goal is to suppress the inflammatory response and prevent organ damage. The main treatment options include:

• Siltuximab (an anti-IL-6 monoclonal antibody): The only FDA-approved treatment for idiopathic MCD (iMCD). It helps improve blood test results and reduces symptoms like fatigue, fever, and weight loss⁵
• Tocilizumab (an IL-6 receptor blocker): Used when siltuximab is not available⁸
• Rituximab: Especially effective for HHV-8-associated MCD⁸
• Corticosteroids: Helpful for sudden worsening of symptoms or as a temporary treatment until other drugs start working
• Immunosuppressive drugs (such as cyclosporine or sirolimus): Used in difficult cases that don't respond to other treatments

Supportive care is equally important. This includes managing anemia, providing nutritional support, offering physiotherapy for fatigue, and addressing mental health challenges associated with chronic illness.

FAQs

Is Castleman's Disease a type of cancer?

No. Although it involves abnormal cell growth, Castleman's Disease is not classified as a cancer. However, patients with MCD have a higher risk of developing lymphoma.

Can Castleman’s Disease be cured?

Unicentric CD can often be cured surgically. Multicentric CD requires long-term therapy and monitoring, but can be controlled in many cases with appropriate treatment.

How do IL-6 inhibitors work?

IL-6 inhibitors like siltuximab block the activity of interleukin-6, a key cytokine in MCD. This reduces inflammation and improves symptoms like fever, fatigue, and weight loss.

How is weight loss in MCD managed?

Nutritional support, control of systemic inflammation, and regular monitoring are key. In severe cases, feeding support may be necessary to restore healthy body weight.

Summary

Fever, fatigue, and weight loss are central systemic manifestations of Castleman's Disease, especially in its multicentric form. These symptoms arise primarily due to IL-6-driven inflammation and contribute significantly to disease burden. Recognising their clinical significance is vital for early diagnosis and optimal treatment. Advances in targeted therapies such as IL-6 inhibitors have improved symptom control and patient outcomes. Nevertheless, ongoing management of nutritional, hematologic, and psychological complications is essential to provide holistic care for those living with this rare and challenging disease.