Approach

Diagnosis is typically made in childhood after presentation with recurrent bacterial and/or fungal infections.

Key history

As CGD patients' mechanism to kill bacteria and fungi is defective, patients often present with a history of recurrent bacterial or fungal infections.

These may include:

  • pneumonia

  • soft tissue abscesses

  • internal abscesses (especially hepatic)

  • oral infections

  • osteomyelitis

  • adenitis

  • BCGosis

  • gastrointestinal (GI) infections or obstruction (secondary to granuloma formation)

  • genitourinary infections or obstruction (secondary to granuloma formation) with symptoms including urgency, flank pain, poor urine stream, pain on urination, bloody urine

  • chronic nasal infections

  • skin infections (i.e., furuncles, impetigo, eczema complicated by infection, perianal abscesses)

  • fatigue

  • symptoms of colitis or other intestinal inflammation (i.e., diarrhea that is sometimes bloody, abdominal pain, nausea, and vomiting).

A history of infection with Staphylococcus aureus, Aspergillus species, Nocardia species, Serratia marcescens, or Burkholderia cepacia is most common and suspicious.[1][3][4][31] Patients do not generally show particularly increased susceptibility to Candida species, although these organisms have occasionally been implicated as a cause of death.[32][31] Disseminated infection after BCG vaccination is well described, and tuberculosis is not uncommon, especially in endemic areas.[33]

Other history may include chronic colitis, sometimes misdiagnosed as Crohn disease, or a history of GI or urinary tract obstruction due to granuloma formation.[4][6][7][8][9][10][11] Of note, skin infections are often frequent and difficult to treat. Chronic lung disease is increasingly recognized in adulthood, including inflammatory lesions, bronchiectasis, scarring, and emphysema.[34][35]

Patients are typically male and show signs and symptoms of disease prior to age 5. There is often a positive family history of either diagnosis with CGD or recurrent, multisystemic infections.

Patients often show mild symptoms despite the presence of serious infection.

Female patients who are carriers of gp91phox mutations often have oral ulcers, a history of discoid lupus, skin rashes, and joint pain.[36] They also frequently describe gastrointestinal symptoms and some may have inflammatory bowel disease.[37] Rarely, female patients may present with typical sequelae (infection and inflammation) of X-CGD as a result of skewed X-inactivation patterns.[38] Patients with p47phox deficiency may have a milder clinical course than other subtypes, but this is not necessarily the case.

Key physical exam findings

Patients often present with infection. Examination may reveal signs of infection, although patients may be asymptomatic or only mildly ill-appearing despite serious infection.[39][40][41] In the absence of infection, general physical exam findings may suggest chronic illness, such as poor growth and chronic lymphadenopathy and hepatosplenomegaly.[39][40]

Signs may include:

  • fever

  • clinical findings of pneumonia (i.e., cough, fever, dyspnea, abnormal lung examination)

  • overt signs of cutaneous infection, adenitis, perianal abscess, or soft tissue abscess (i.e., red skin lesion, perianal pain)

  • signs of oral infection

  • skin scarring related to previous abscess drainage or biopsies

  • chorioretinal lesions

  • hepatomegaly, splenomegaly.

Routine labs and imaging

Tests include routine laboratory tests (CBC, ESR, and CRP) and imaging (CT, ultrasound, PET scan), along with procedures to identify the infectious agent. The diagnostics currently used for invasive aspergillosis have low sensitivity in CGD patients.[32]

Chronic anemia is common (low Hb, low Hct), and ESR and CRP may be elevated during infection. Inflammatory markers may be misleading as they tend to rise and fall in relation to chronic inflammatory processes, even in the absence of infection.

During active infection, prompt imaging, such as CT or ultrasound imaging, is useful to localize and evaluate the extent of infection. Whole body F-18 fluorodeoxyglucose (FDG) PET is helpful in differentiating active infectious processes from past infections or chronic inflammatory lesions.[42] Endoscopy, especially colonoscopy, may be required to evaluate the activity of inflammatory colitis. MRI is useful in cases of suspected osteomyelitis. Brain imaging with MRI should be considered in patients with disseminated Aspergillus or Nocardia infections.[43]

With increasing recognition of chronic lung disease in CGD, many clinicians now perform routine chest CT scans, for example every 5 years. Abnormal lung function tests can point toward chronic lung disease.[35]

Fecal calprotectin levels correlate with colitis severity and can be used to monitor activity.[44]

Confirmatory testing

When suspected in patients with a consistent medical history, referral to a specialist is imperative for diagnostic testing. Diagnosis is typically made by identifying abnormal neutrophil oxidative burst activity. The first of two common methods is the nitroblue tetrazolium (NBT) test, in which normal neutrophils reduce nitroblue tetrazolium to formazan, a dark blue pigment visible on microscopic inspection.[45][46] Neutrophils of patients with CGD do not reduce nitroblue tetrazolium.

The second method, the dihydrorhodamine (DHR) 123 test, utilizes flow cytometry to detect the oxidation of dihydrorhodamine 123 in activated neutrophils. This test differentiates between X-linked and autosomal recessive forms as well.[47][48][49]​ The X-linked form is typically associated with an absence of detectable oxidative burst activity, while autosomal recessive forms are usually associated with a decreased DHR shift and a wide-based histogram. Subsequent tests include Western blot or flow cytometric analysis of individual NADPH oxidase components. Genetic analysis is used to confirm the diagnosis.[50]​ If there are existing genetic test results, do not perform repeat testing unless there is uncertainty about the existing result, e.g., the result is inconsistent with the patient’s clinical presentation or the test methodology has changed.[51]

Following the diagnosis of male patients with X-linked CGD, maternal testing is recommended.[Figure caption and citation for the preceding image starts]: Sample DHR histograms. Neutrophils were incubated with dihydrorhodamine 123 (DHR 123) and then activated with phorbol 12-myristate 13-acetate (PMA). On activation, DHR 123 is oxidized to highly fluorescent rhodamine 123 in normal neutrophils. Pre-activation histograms are shown on the left and post-activation histograms on the right. Block A shows normal response, with a large rightward shift in mean fluorescent intensity. Block B shows a patient with X-linked CGD lacking a detectable oxidative burst. Block C shows the mother of an affected patient with 2 populations of neutrophils, one normal and one with mutated gp91phox. Block D shows the typical pattern observed in patients with autosomal recessive CGD. Patients with autosomal recessive CGD can also rarely display an absence of oxidative burst activity, as shown in Block E.Permission by CCHMC clinical diagnostic immunology lab [Citation ends].com.bmj.content.model.Caption@79f19eb9

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