A neutrophil defect, prediposes to certain characteristic organisms. Frustrated neutrophils cause granulomas, hence the name: these are responsible for some other characteristic features of the disease.
Due to NADPH oxidase mutations, causing reduced oxidative burst (needed by neutrophils to kill pathogens after phagocytosis). Various types depending on which subunit affected. X linked gp91phox def (ie NADPH OXidase, due to CYBB gene defect) is severe, p47phox is autosomal and milder (NCF1 gene, partial activity retained). Other gene defects are CYBA and NCF2, funnily enough, and RAC2. Phenotype varies even between mono twins (factors?). Since non-oxidative killing is then the only remaining immune mechanism, the most important pathogens are catalase positive (an enzyme to make bugs resistant to the peroxide and superoxide produced by neutrophils or by the bacteria themselves as a toxic byproduct). Register exists in UK.
Usually present by 2 yrs but occ not until adulthood. Most commonly lymphadenitis (often culture negative), skin infections (esp perianal), pneumonia. Hepatomegaly is a clue. Other sites of infection are osteomyelitis, liver abscesses (distinctive, fibrous capsule, septated, thick contents – vague presentation, blood cultures usually negative so low index of suspicion).
Probably not the superoxides themselves that are important; MPO deficiency does not tend to present with infections! Critical step is probably degranulation of primary granules, with release of elastases etc. Superoxides probably deal with toxic metabolites rather than doing the killing.
Chronic inflammatory problems occur (due to having intact upregulated phagocytic activity with reduced apoptosis):
- BCG causes lymphadenitis in CGD, but does not disseminate.
- colitis (characterized by pigment laden macrophages, quite specific for CGD but not very sensitive). Seen in 45% of X-linked, 10% of autosomal recessive. Tends to present with abdo pain rather than frank bleeding, often subclinical, may account for FTT.
- lupus like rash and illness
- Poor wound healing (classically dehiscence at 10/7 post op, non-purulent)
- Hollow organs may become obstructed by granulomas esp oesophagus, gastric outlet, bladder.
- pulmonary fibrosis
Mums who are carriers of CGD can be symptomatic even with fairly decent percentages of functional neutrophils incl aspergillus! Due to lyonization. Onset variable.
Nitroblue tetrazolium (NBT) test now replaced by Dihydrorhodamine test on flow cytometer (false positive esp in preterm so always check with reference lab). Only takes 15 mins!
The organisms found are also characteristic:
- Staphylococcus aureus – found in most liver abscesses as well as in skin
- Enterobacteria – Enterobacter, E coli, Salmonella, Klebsiella, Aerobacter, Serratia, Yersinia, Proteus
- Aspergillus – mostly fumigatus but A. nidulans is emerging in US, and Candida albicans, Scedosporium apiospernum and Chyrosporium zonatum reported. Can be acute, esp after inhalation eg digging in garden. Biopsy may be needed to make diagnosis. Steroids useful for severe inflammatory disease!!!
- Burkholderia cepacia – looks identical to Pseudomonas, so any Ps not specified as aeruginosa should be considered suspect! (Pseudomonas itself is catalase positive but susceptible to non-oxidative killing so is not a problem).
- Septicaemia is v rare ! – but may be seen with B. cepacia.
- Nocardia common in US, rare in Europe – gram positive soil organism, forms filaments like a fungus. Usually pneumonia but also skin, CNS. Sensitive to co-trimoxazole.
- Actinomycosis – even though catalase negative!
Note that you do NOT see PCP, strep, onychomycosis (despite susceptibility to fungus) or lymphomas (cf granulomas).
Patients are often anaemic with an iron-deficient pattern but resistant to iron supplementation (except in bowel disease, ?vitamin B12 def). ESR is often raised even when well. Less of a problem with CRP.
Co-trimoxazole prophylaxis (daily dosing, not 3x weekly as in PCP prophylaxis) good because active against typical bugs, and intracellular. Itraconazole is prophylactic vs Aspergillus.
Avoid BCG because of tendency to form abscess.
Cipro and Fluclox good for first line – effective against typical organisms, and cipro acts intracellularly. In serious pneumonia, empirical treatment should consist of Ceftazidime/Meropenem, Fluclox and Amphotericin. Because of the range of possible organisms, bacteriological diagnosis should not be delayed and tissue biopsy sought if non-invasive methods unsuccessful.
Steroids for colitis, cystitis and obstructive granulomatous disease. Also for poor wound healing!
- Voriconazole is an effective oral antifungal, so useful when no tissue diagnosis (beware accumulation of amphotericin with long term use, causing permanent renal damage).
- Interferon (IFN) gamma – effective as prophylaxis in large Multicentre study, but strong centre effect with less benefit in Europe (in fact the lowest incidence seen with antibiotic prophylaxis) so not universally used (but safe). Less evidence in established infection but that’s when it tends to get used! Increases NO production by neutrophils, by improved RNA splicing efficiency(?). Give three times a week by subcut injection; side effect is fever and flu-like symptoms. Better antifungals mean it is used less now.
- Granulocyte infusions (apheresed from donors after GCSF priming) can be done every 1-2 days (or instilled directly into lesions) but rarely needed now with better antifungals. Increases risk of reaction to Ambisome, plus you become sensitized, which will hinder transplant prospects. Can support infected kids through BMT.
- Surgery may be necessary to remove infected tissue, may help get positive culture.
- BMT is indicated at diagnosis if a matched donor is available.
- Gene therapy has produced transient improvements only.
Median survival 30 years – NB compliance with prophylaxis by adolescents. So consider transplant.
[Clin Exp Imm 122(1); October 2000 pp 1-9 GOLDBLATT, D; THRASHER, AJ]