Chronic granulomatous disease (cgd)

CHRONIC

GRANULOMATOUS DISEASE

(CGD)

Duncan Mapeto Banda

Physiotherapy student

Malawi college of medicine

Physiotherapy department

Lecture objectives

• CGD definition

• Epidemiology & Causes

• Mode of inheritance & Genes involved

• Pathophysiology

• Signs & Symptoms

• Diagnosis and Treatment

CGD

• An inherited disease whereby phagocytes

ingest microbes but cannot kill them.

• Leads to formation of granulomas and

recurrent infections.

Epidemiology

• The hallmark of (CGD) is early onset of

severe recurrent bacterial and fungal

infections.

• The most commonly involved organs are

those that serve as barriers against the entry

of microorganisms from the environment,

e.g. the skin, lungs, GI tract, lymph nodes,

liver, and spleen.

Chronic presentation of CGD

• Granuloma formation in the GI

E.g. dysphagia, nausea, vomiting and abdominal pain

Granulomas, nodular masses of inflammatory tissue, form in response to persistent antigenic stimulus (chronic infections) or because of lack of negative feedback by oxygen radicals on proinflammatory cytokines.

In every 140 patients with chronic granulomatous disease, 33% had GI involvement

Continued...

• Granuloma of genitourinary (GU)

Symptoms of GU obstruction include

dysuria, incontinence, abdominal

discomfort, and urinary retention.

NB: Skin infections or granulomatous

dermatitis occurs in almost two thirds of

patients.

Pathogenesis of CGD

• Fungal causation occur in up to 20% of patients with CGD

• Pneumonia is the most common presentation

NB: Infections are caused mostly by catalase positive organisms, such as Aspergillus spp. or Staphylococcus spp., and are often life-threatening.

• Aspergillus species infection in CGD is often indolent, with mild or absent symptoms at the outset.

Causes

• Mutation of CYBA, CYBB, NCF1,NCF2

and NCF4 genes which code for subunits of

NADPH oxidase

NADPH oxidase plays a role in immune

system

NADPH oxidase Hydrogen

peroxide (kills engulfed microbes)

Mode of inheritance

• X-linked reccessive pattern

CYBB is located on X-chromosome

More males affected than females

Heterozygous carriers

Homozygous recessive

(suffers)

Homozygous dominant

(normal)

Continued.....

• Autosomal recessive pattern

Involved CYBA, NCF1, NCF2 & NCF4

Equal chance of occurrence in males and

females

No signs & symptoms

in carriers

Continued....

• Among those with GI involvement, 89% had X91 versus 11% with autosomal recessive chronic granulomatous disease.

• However, carriers of X-CGD have a notable incidence of discoid lupus erythematosus, photosensitivity, Raynaud phenomenon, and aphthous ulcers.

Pathophysiology

• Phagocytes ingest microbes but fail to kill

them

• Killing of microbes is mediated by NADPH

oxidase also called phagocyte oxidase

(phox).

• When this is non functioning there is a

defect in the killing mechanism.

Phagocyte Defect

• The NADPH oxidase is a key component of

human innate host defences.

• In phagocytes, this enzyme complex is

activated to produce superoxide anion and

other secondarily derived ROS (reactive

oxygen species)

• NADPH − 2 e− + 2O2 −> NADP+ + H+ + 2 .O2−

Continued…..

• All animals release superoxide (O2−) during

respiration

• Superoxide dismutase (SOD) converts O2−

into hydrogen peroxide (H2O2)

• H2O2 is used to kill pathogens

• Some pathogens e.g staphlococus aureaus

are catalase positive

• They release catalase and O2−

Continued....

• Therefore patients with CGD experience

severe recurrent bacterial and fungal

infections due to accumulation of

phagocytes containing ingested bacteria.

• Apoptosis/turnover is abnormal.

Signs & Symptoms

• Pneumonia

• Prolonged infections

– skin, liver, bone & joints, etc.

• Hepatomegaly & splenomegaly

• May develop WBC clusters

Note: Most people diagnosed during early life

Diagnosis

• Chest therapy

• Nitroblue tetrazolium test

• Hydrogen peroxide amount test

Treatment

• Antibiotic therapy

– Antifungal; itraconazole & Amphotericin B

– Antibacterial; Trimethoprim

• Granulocyte transfusions from GCSF

• Hematopoietic stem cell transfusions

– From a matched donor

• Surgery to treat abscesses

• Gene therapy ? ? ?

Infection reduction measures

• Garden exposure limits

• No swimming other than in Chlorinated

water

• No Marijuana smoking

– Has Aspergillus spp

21

References

• www.myoclinic.com

• http://www.patient.co.uk/doctor/chronic-granulomatous-

disease

• https://rarediseasesnetwork.epi.usf.edu/PIDTC/CGD

• http://www.nlm.nih.gov/medlineplus/ency/article/001239.h

tm

• http://ghr.nlm.nih.gov/condition/chronic-granulomatous-

disease

• http://www.cgdsociety.org/