Fungal Infections

Immunotherapy

Several recombinant growth factors, cytokines and interferons are available for clinical use, although none has a formal approved indication for fungal infection. There are some data indicating benefit however. Immunoglobulin infusions are not useful for any fungal infection.

White cell infusions

White cell transfusions (or buffy coats) may be helpful, but the quantity of neutrophils (granulocytes, phagocytes) transfused is critically important, preferably >40x109. Granulocyte colony-stimulating factor (GCSF) use has increased the granulocyte yield by approximately four-fold, and increases cell longevity (delays apoptosis). Granulocyte transfusions can be helpful in controlling severe infections progressing despite the use of appropriate antibiotics, with responses of 40-80% depending on patient characteristics. Benefit is limited to a small number of patients as the incidence of prolonged reversible neutropenia (<100-200/109) in whom severe neutropenia is expected to persist for >5-7 days is relatively small. Severe side effects are rare. Checking bone marrow in potential recipients to determine the persistence of leukemia and/or the likelihood of endogenous

marrow recovery is advisable, to avoid transfusing granulocytes to no avail. Non-alloimmunised patients can receive cells from nonmatched ABO compatible donors.  Alloimmunized patients should receive granulocytes from either HLA-matched donors or donors selected by leukoagglutination or lymphocytotoxicity crossmatching.

Platelets (an essential component of clotting) have a significant impact on Aspergillus hyphae outside the body, and platelet infusions given to prevent bleeding could have a clinical impact in patients with invasive aspergillosis, but this has not yet been shown in patients.

Granulocyte colony stimulating factor (GCSF)

GCSF stimulates the production of neutrophils (granulocytes, phagocytes) by the bone marrow as well as influencing other parts of the immune system. As neutropenia (granulocytopenia) is a major risk factor for invasive aspergillosis, shortening the period of neutropenia with GCSF is valuable in prevention, or possibly early therapy of invasive aspergillosis and other filamentous fungal infections. Several studies show this. GCSF has some negative effects, notably in depressing TH1 responses and if circulating neutrophils rise too fast and too high in patients who do have invasive aspergillosis, lung haemorrhage (bleeding) is more frequent, which may be fatal.

A randomized study of GCSF for candidaemia was inconclusive, with a suggestion of benefit for those with candidaemia and a worse outcome for those with Candida peritonitis, all non-significant findings.

In practice, GCSF is used in neutropenic patients (predicted >10 days) to accelerate the recovery of neutrophils, and treatment is stopped when neutrophil recovery has occurred.

Gamma interferon

Gamma interferon (gIFN) upregulates phagocytosis and the respiratory burst activity of monocytes and macrophages enhancing the killing mechanism of these cells. gIFN enhances the ability of the phagocytic cells to produce other proinflammatory cytokines, thus, IFN-y acts in a positive feedback loop that represents an important amplifying mechanism in the inflammatory response to infections. gIFN is available clinically as prophylaxis against infection in patients with the rare inherited immune deficiency chronic granulomatous disease. gIFN reduced the number and severity of infections by 70%, regardless of antibiotic prophylaxis or genetic subtype.

For cryptococcal meningitis, a higher 2-week culture conversion rate was seen in those receiving 100 or 200 mg of gIFN than in placebo recipients with a trend toward improved combined mycologic and clinical success[1]. Adjunctive recombinant interferon-gamma therapy has been tried in C. gattii infection unresponsive to repeated/prolonged courses of antifungal drugs. Its contribution to outcomes is uncertain. Therefore there may be a role for gIFN in cryptococcal meningitis or cryptococcoma, but it is not certain.

Resistance to Aspergillus infection is dependent on the development of CD4+ TH1 protective immunity and the production of gIFN. Some uncontrolled clinical data suggest a potential role of gIFN in prevention and treatment of invasive aspergillosis. gIFN is regarded as a rescue therapy for patients with refractory invasive fungal infections that fail conventional antifungal treatment. The benefit of adding gIFN for treating invasive aspergillosis has been documented in several studies and case reports. No randomized trials have been conducted.



[1] Pappas PG, Bustamante B, Ticona E, Hamill RJ, Johnson PC, Reboli A, Aberg J, Hasbun R, Hsu HH. Recombinant interferon- gamma 1b as adjunctive therapy for AIDS-related acute cryptococcal meningitis. J Infect Dis 2004;189:2185-91.

 

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