Kostmann Disease Treatment & Management

Updated: Aug 24, 2017
  • Author: Peter N Huynh, MD; Chief Editor: Harumi Jyonouchi, MD  more...
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Treatment

Medical Care

Antimicrobial prophylaxis

Antimicrobial prophylaxis may be useful in preventing recurrent infections. Oral sulfamethoxazole/trimethoprim sulfate (Bactrim) as a once daily, 50 mg/kg/d dose has been used. This only partially prevents the gingivostomatitis associated with severe congenital neutropenia. Concurrent therapy with metronidazole, which covers oral saprophytic flora, especially anaerobes, also may be added.

Hematopoietic growth factors

Hematopoietic growth factors (granulocyte colony-stimulating factor [G-CSF] and granulocyte macrophage colony-stimulating factor [GM-CSF]) are used to correct neutropenia. G-CSF has been used since the late 1980s and has shown a greater than 90% response rate. G-CSF is more efficacious and tolerable than GM-CSF, with less flu-like syndrome and less marked eosinophilia. There are 2 forms of G-CSF available: filgrastim (Neupogen in 480- or 330-µg vials) and lenograstim (Granocyte in 340- or 130-µg vials). Lenograstim is the glycosylated form of G-CSF.

Pegfilgrastim (Neulasta)

Pegfilgrastim is the pegylated, covalent conjugate of G-CSF, a combination of filgrastim and polyethylene glycol, with a half-life of 15-80 hours, which decreases the number of injections needed from daily to once weekly. Pegfilgrastim has been shown to be clinically efficacious and improve compliance and quality of life in various case reports. [23, 24, 25] However, in an observational study of 17 patients from the French Severe Chronic Neutropenia Registry who received pegfilgrastim, only half the patients prescribed were able to continue this medication long term because of adverse events and lack of efficacy. [26] Further studies evaluating long-term outcomes are required.

Filgrastim/lenograstim (G-CSF)

There is an induction phase with G-CSF to evaluate the response of individuals, with an increase in absolute neutrophil count (ANC) (>1500/μL) and clinical improvement after 10-15 days. The initial daily dose is 5 μg/kg subcutaneously. If there is no response after 15 days, the daily dose is increased by 5 μg/kg. If the response is rapid or excessive (ANC >5000 /μL), the dose is halved. Once the minimal daily dose is determined, the maintenance phase can begin, with monitoring of neutrophil counts every 3-6 months. Almost two thirds of patients respond to a daily dose of 2-10 µg/kg, while 20% respond to 10-20 μg/kg. A small percentage of patients require higher doses, up to 100 μg/kg. Around 10% of patients are unresponsive to G-CSF therapy. [8]

Short-term tolerability

G-CSF has good short-term tolerability with occasional immediate and local reactions (< 1 per 100). Flu-like reactions are another infrequent adverse effect. Bone pain occurs in 2-5% of patients, which resolves within 24 hours and does not recur with lower doses. [5]

Long-term tolerability

G-CSF acts principally on granulocytes, but various blood cell abnormalities can be seen transiently during treatment. Monocytosis (above 1500/μL) is frequent and eosinophilia can be amplified by G-CSF, but lymphocytosis and hemoglobin levels are usually not affected. Occasionally, reticulocytosis and elevated hemoglobin levels can be seen if there is an initial inflammatory anemia at the start of treatment.

Thrombocytopenia is the most common hematologic adverse effect and is usually moderate and resolves when the G-CSF dose is reduced. Thrombocytopenia can also be from hypersplenism. The spleen is usually enlarged at the start of treatment. Spleen rupture requiring splenectomy can sometimes occur.

Uricemia can arise from long-term treatment but has no clinical consequences. Gout exacerbations have been seen in short-course therapy, however.

The first cases of leukocytoclastic vasculitis were seen after short-term G-CSF treatment and seem to be due to the increase in neutrophil adhesion molecule expression.

Two cases of mesangioproliferative glomerulonephritis have been seen with long-term treatment, but they resolved after dose reduction or stoppage of treatment.

Osteoporosis occurs in up to one fourth of patients with severe congenital neutropenia who receive G-CSF therapy, and 2 cases of pathological fractures have been reported. However, severe congenital neutropenia alone seems to be associated with osteopenia, which is usually present before treatment starts.

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Surgical Care

Surgical drainage of abscesses may be required for infections refractory to intravenous antibiotics.

Hematopoietic stem cell transplantation (HSCT) can be curative for severe congenital neutropenia and is the only option when patients continue to have severe infections despite G-CSF therapy. HSCT is indicated when there is G-CSF resistance (>50 μg/kg/day) and myelodysplasia/leukemic transformation.

Patients chronically dependent on high doses of G-CSF (at least 20 μg/kg per injection at least 3 months a year) should be considered for bone marrow grafting on a case-by-case basis since there is a high risk of leukemic transformation, taking into account whether related donors are available. Survival with HSCT is now is over 70%, even with malignant transformation in most cases.

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Consultations

A pediatric immunologist, pediatric hematologist, and pediatric dentist are helpful consultations.

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Diet

Historically for oncology patients, the neutropenic diet has reduced the introduction of bacteria into the host's gastrointestinal tract, thus minimizing the patient's exposures to potential pathogens. This diet excludes foods considered at high risk for bacterial colonization, especially raw fruits and vegetables. The Neutropenic Diet Guideline includes the following recommendations:

  • Avoid raw vegetables and fruit (Oranges and bananas are acceptable.)

  • Avoid take-out foods, fast foods, and fountain drinks

  • Avoid aged cheese (bleu, Roquefort, brie)

  • Cook all produce to well done; eggs must be hard-boiled

  • Avoid deli meats

  • No raw nuts, nuts roasted in shell, or freshly ground nut butters from a health food store

  • No well water

  • No yogurt

No dietary restrictions are necessary in patients with severe congenital neutropenia, so long as they are on adequate doses of G-CSF and their ANCs are maintained above 1000/μL.

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