Chronic Granulomatous Disease

Chronic granulomatous disease is a rare genetic condition that weakens the immune system’s ability to fight certain infections, leaving people vulnerable to serious bacterial and fungal infections throughout their lives.

Table of contents

• What is chronic granulomatous disease?
• How common is CGD?
• Symptoms and signs
• Causes and genetics
• Complications
• Diagnosis
• Treatment
• Preventing infections
• Outlook and life expectancy

What is chronic granulomatous disease?

Chronic granulomatous disease (CGD) is a genetic condition in which certain white blood cells (the cells that help fight infections) don’t work properly. These special white blood cells are called phagocytes, and they include neutrophils, monocytes, macrophages, and eosinophils. When phagocytes work normally, they catch and destroy harmful bacteria and fungi that enter the body^[1].

Bridges-Good syndrome, chronic granulomatous disorder, Quie syndrome

In people with CGD, these white blood cells cannot produce certain chemicals, particularly superoxide and hydrogen peroxide, which are needed to kill bacteria and fungi. Without these chemicals, the immune cells can’t destroy certain types of germs. This means people with CGD are much more likely to get serious infections from bacteria and fungi that a healthy immune system would normally fight off^[2].

The name “granulomatous” comes from what happens when the body tries to fight these infections. As immune cells keep gathering at infection sites but fail to kill the germs, they form large clusters called granulomas. These are hard lumps made up of many immune cells. While some granulomas are tiny and can only be seen under a microscope, others grow large enough to be felt or seen, and can block organs like the bowel or urinary tract^[5].

The good news is that people with CGD can defend against most infections. They have normal immunity to most viruses and can fight off many types of bacteria and fungi. This is why they are not sick all the time. They may go months or even years without infections, and then suddenly have a severe one^[5].

How common is CGD?

CGD is a rare disease. It affects approximately 1 in 200,000 to 250,000 people worldwide. About 20 new cases are diagnosed each year in the United States. The condition occurs more often in males than females^[2][3].

Symptoms and signs

People with chronic granulomatous disease usually show signs of illness during childhood, although some people may not be diagnosed until they are teenagers or adults. Most people with CGD are diagnosed before age 5^[1][4].

The most common symptom is having serious bacterial or fungal infections every few years. A person with CGD typically has at least one serious infection every 3 to 4 years^[3]. The infections can be life-threatening if not treated promptly.

• Lungs
• Skin
• Lymph nodes
• Liver
• Stomach and intestines
• Bones
• Brain
• Eyes
• Spleen
• Kidneys
• Bladder

Common infection sites

The lungs are the most frequent area of infection. Pneumonia (lung infection) is very common in people with CGD. A special concern is a type of fungal pneumonia called mulch pneumonitis, which happens after being exposed to decaying plant materials like mulch, hay, or dead leaves. This causes fever and shortness of breath^[3].

Other common sites of infection include the skin, liver, lymph nodes, bones, stomach, intestines, and urinary tract^[1][2].

Infection symptoms

When infections occur, people with CGD may experience^[1]:

• Fever
• Chest pain when breathing in or out
• Swollen and sore lymph glands
• Constant runny nose
• Skin irritation including rash, swelling, or redness
• Swelling and redness in the mouth
• Trouble swallowing
• Itchy, irritated skin

Digestive problems

Many people with CGD develop inflammation in the gastrointestinal tract. The intestinal wall can become inflamed, causing a form of inflammatory bowel disease that can range from mild to severe. This can lead to^[1][3]:

• Stomach pain
• Diarrhea
• Bloody stool
• Nausea and vomiting
• Weight loss
• Painful pockets of pus near the anus (abscesses)

Inflammation in the stomach can prevent food from passing through to the intestines, leading to vomiting after eating and difficulty digesting food^[3].

Organisms that commonly cause infections

People with CGD are sometimes infected with germs that usually don’t cause disease in people with normal immune systems. The most common disease-causing organisms are^[4]:

Bacteria (particularly those that produce an enzyme called catalase):

• Staphylococcus aureus
• Serratia marcescens
• Listeria species
• E. coli
• Klebsiella species
• Burkholderia cepacia
• Nocardia

Fungi:

• Aspergillus species (especially Aspergillus fumigatus)
• Candida species

Patients with CGD can usually resist infections from bacteria that don’t produce catalase. However, they are very susceptible to bacteria and fungi that do produce this enzyme^[4].

Causes and genetics

CGD is a genetic condition, which means you inherit it from one or both of your biological parents. You are born with it, and it is not contagious like a cold^[2][6].

The condition is caused by changes (mutations) in genes that make parts of an important enzyme complex called NADPH oxidase. This enzyme plays an essential role in the immune system by helping white blood cells produce toxic substances like superoxide that kill bacteria and fungi^[3].

Mutations in five different genes can cause CGD: CYBB, CYBA, NCF1, NCF2, and NCF4. Each of these genes provides instructions for making different parts of the NADPH oxidase complex^[3].

Types of CGD inheritance

There are two main ways CGD can be passed down to a child^[6]:

X-linked CGD: This is the most common type, accounting for about 70% of cases in the United States. It involves a mutation in the CYBB gene located on the X chromosome. Because males have only one X chromosome, they are much more likely to be affected if they inherit the mutated gene from their mother. The mother is called a carrier because she has one normal X chromosome and one with the mutation. X-linked CGD almost always affects males^[2][5].

Autosomal recessive CGD: This type occurs when both parents pass on a faulty gene to their child. In this case, both parents are carriers of CGD. They each have one normal copy of the gene and one copy that doesn’t work right. When both parents pass on the faulty gene, the child develops CGD. This type affects males and females equally^[5][6].

X-linked carriers

Females who carry the X-linked gene may experience health problems themselves. They may have autoimmune problems, like lupus of the skin, and sometimes may have serious infections. It is important for female carriers to be monitored, as their immune function can change over time and lead to an increased risk of CGD symptoms, including infections and inflammatory bowel disease^[5].

Complications

CGD can lead to several serious complications beyond the infections themselves^[2][3]:

• Difficulty digesting food due to abscesses and inflammation in the intestines
• Inflammatory bowel disease (IBD), which causes ongoing inflammation in the digestive tract
• Growth problems in infants and children
• Abscesses (pus-filled pockets) in organs like the liver, lungs, skin, or spleen
• Blockages in the bowel or urinary tract from large granulomas
• Inflammation of lymph nodes and bone marrow, which can further weaken the immune system

Depending on which gene mutation causes CGD, a person may be at higher risk for heart and kidney disorders, diabetes, or certain autoimmune conditions^[2].

Rarely, people with CGD develop autoimmune disorders, which occur when the immune system malfunctions and attacks the body’s own tissues and organs^[3].

Diagnosis

To diagnose CGD, a healthcare professional will review your family and medical history and perform a physical exam. During the physical exam, doctors can look for signs of inflammation and granulomas^[2][9].

Diagnostic tests

Neutrophil function tests: A healthcare professional may do a test called the dihydrorhodamine 123 (DHR) test or similar tests to see how well neutrophils are functioning. The DHR test is commonly used to diagnose CGD because it can detect whether white blood cells are able to produce the chemicals needed to kill germs^[2][9].

Genetic testing: A genetic test can confirm the presence of a specific genetic mutation that causes chronic granulomatous disease. This test identifies which gene is affected and what type of CGD a person has^[9].

Prenatal testing: If one child in a family has already been diagnosed with CGD, healthcare professionals may offer prenatal testing during pregnancy to see if another child will be affected^[9].

Early diagnosis is very important because people with CGD can be placed on preventive antibiotics and antifungals to help ward off infections before they occur^[4].

Treatment

Treatment for CGD is aimed at helping people avoid infections and manage the condition when infections do occur. With proper treatment, most people with CGD can live relatively normal lives^[9].

Infection prevention and management

The main approach to treating CGD involves lifelong use of medications to prevent infections. These preventive medicines typically include^[2][9]:

• Antibiotics: Such as trimethoprim-sulfamethoxazole (Bactrim, Sulfatrim Pediatric) to prevent bacterial infections
• Antifungal medicines: Such as itraconazole (Sporanox, Tolsura) to prevent fungal infections

When infections do occur, they must be treated aggressively with broad-spectrum antibiotics or antifungals. Treatment should be started at the first signs of infection. Every episode of fever must be treated promptly, and doctors should use drugs that can cross into white blood cells. Initial treatment should include at least two antibiotics to cover both gram-positive and gram-negative bacteria. If there is no improvement within 48 hours, changes in treatment may be needed, including adding an antifungal drug^[14].

Treatment should be continued for weeks or months, even when there is significant improvement, in order to completely eliminate the infection^[14].

Interferon-gamma therapy

People with CGD may receive regular injections of interferon-gamma, a protein that helps boost cells in the immune system to fight infections. This treatment can help reduce the frequency and severity of infections^[9].

Stem cell transplantation

For some people, a stem cell transplant (also called bone marrow transplant) can provide a cure for CGD. This procedure involves replacing the patient’s faulty immune cells with healthy cells from a donor. The decision to use stem cell transplantation depends on several factors, including the person’s age, the severity of their disease, and whether a suitable donor is available^[9].

Managing inflammation

Treatment for inflammatory complications in patients with CGD can be challenging because many anti-inflammatory medicines suppress the immune system, which is already impaired. Many patients respond well to corticosteroids, but they may require prolonged courses. Other medicines like sulfasalazine and azathioprine can help reduce the need for steroids^[14].

Preventing infections

People with CGD need to take extra steps to avoid exposure to bacteria and fungi that could cause serious infections. These harmful germs can be found in many everyday places^[6][15]:

• Soil, mulch, and gardens
• House plants and potting soil
• Woodchips and playgrounds
• Standing water, lakes, and ponds
• Dust from new construction
• Carpets and pets
• Mold in barns, sheds, basements, and caves
• Yard debris like piles of leaves or grass clippings

Practical prevention tips

To help prevent infections, families can take several steps^[15]:

In the home:

• Install exhaust fans in bathrooms to prevent mold growth
• Use strong cleaners including bleach to kill fungi and bacteria
• Keep shoes outside or in a designated area by the door
• Keep house plants outside, as potting soil can contain fungi
• Stay out of the home while carpet is being removed or replaced
• Dust and clean regularly

Daily habits:

• Wash hands frequently and use hand sanitizer
• Avoid jumping in leaf piles during fall
• Stay away from dusty, windy conditions
• Avoid basements that are moist, moldy, or smell funny
• Take all prescribed medicines consistently

Outdoor activities: While it’s important to take precautions, children and adults with CGD should still be allowed to enjoy life. The key is finding the right balance between safety and living fully^[15].

Outlook and life expectancy

With modern treatment including preventive antibiotics, antifungals, and interferon-gamma therapy, the outlook for people with CGD has improved significantly. Early diagnosis and aggressive treatment of infections can greatly improve outcomes^[14].

Repeated episodes of infection and inflammation can affect life expectancy. However, with proper treatment and careful management, most people with CGD live into mid- to late adulthood. Many lead relatively normal, active lives with appropriate precautions and medical care^[3].

The severity of CGD can vary considerably. Some people have frequent severe infections, while others may have milder disease with less frequent infections. The type of genetic mutation and how early the diagnosis is made can influence the disease course^[8].

Support from healthcare teams, family, and patient communities plays an important role in helping people with CGD manage their condition and maintain quality of life.