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Empiric Antibiotics in Febrile Neutropenia: How Long?

Aguilar-Guisado M, Espigado I, Martín-Peña A, et al. Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open-label, randomised, controlled phase 4 trial. Lancet Haematol 2017; 4:e573-e583.

The 2010 Infectious Disease Society of America (IDSA) guidelines dealing with fever and neutropenia recommend the following regarding the duration of empiric antibacterial therapy: “In patients with unexplained fever, it is recommended that the initial regimen be continued until there are clear signs of marrow recover; the tradition endpoint is an increasing ANC [absolute neutrophil count] that exceeds 500 cells/mm³ (B-II)” [1]. Less often followed by clinicians is the weaker recommendation that immediately follows: “Alternatively, if an appropriate treatment course has been completed and all signs and symptoms of a documented infection have resolved, patients who remain neutropenic may resume oral fluoroquinolone prophylaxis until marrow recovery (C-III).” More recently, the European Society for Clinical Oncology made the following recommendation [2]: “If the ANC is ≤0.5 x 10⁹/L, the patient has no complications and has been afebrile for 5–7 days, antibacterials can be discontinued except in certain high-risk cases with acute leukaemia and following high-dose chemotherapy when antibacterials are often continued for up to 10 days, or until the ANC is ≥0.5 x 10⁹/L (II, A)”.

The How Long study was an open-label, randomized, phase 4 superiority trial performed at 6 Spanish academic centers that was designed to evaluate the safety and efficacy of early discontinuation of empiric antibiotic therapy (EAT) despite persistence of neutropenia in patients in whom an etiologic pathogen was not identified. A total of 157 adults with hematological malignancy or hematopoietic stem cell transplantation who had high-risk neutropenia (ie, expected to last for ≥7 days) were randomized (1:1). Empiric therapy consisted of an antipseudomonal ß-lactam with or without a second antibiotic (aminoglycoside, fluoroquinolone, and/or vancomycin). In patients randomized to the experimental group, EAT was discontinued when they had clinically recovered and had been afebrile for 72 hours, regardless of lack of neutrophil recovery. Empiric antibiotic therapy was not discontinued in the control group until their ANC was ≥0.5 × 10⁹/L. Antibacterial prophylaxis other than cotrioxazole was not routinely used at the participating centers.

The mean number of days free of EAT in the intent-to-treat population, the primary endpoint of the study, was significantly greater in the experimental group (16.1 days) than the control group (13.7 days) with an absolute difference of −2.4 days (95% confidence interval [CI], −4.6 to .3; P = 0026). Serious adverse events occurred less frequently in the experimental group than the control group: 18 and 38, respectively. At least 1 episode of recurrence of fever occurred in 11 (14%) experimental and 14 (18%) control patients; a pathogen was identified in 6 of 11 and 6 of 14 of these, respectively (although several were fungal). One experimental group patient and 3 control group patients died, but none of the deaths were due to bacterial infection.

The results of How Long are compatible with at least 2 trials in pediatric patients, as well as with a retrospective analysis of the management of adults with allogeneic hematopoietic stem cell transplants. In the latter, there was no significant difference in outcomes among patients who received ≥5 days of broad-spectrum EAT and whose antibiotics were discontinued when afebrile despite continued neutropenia when they were compared with those in whom antibiotics were continued [3].

Thus, the available data demonstrate the safety of discontinuation of EAT initiated in patients with febrile neutropenia of unknown cause who become afebrile but remain neutropenic. Furthermore, they extend the 2016 European recommendation to include high-risk patients, and they also extend the weak alternative IDSA recommendation to include patients not receiving fluoroquinolone prophylaxis.

Eliminating unnecessary antibiotic exposure has multiple obvious benefits. This may be especially true of allogeneic hematopoietic stem cell transplant recipients, given the accumulating data demonstrating a relationship between alterations in the gastrointestinal microbiome, including reduced ecological diversity, and increased risk of acute graft-versus-host disease and of mortality [4].

References

A Novel Mechanism of Immune Evasion by Plasmodium falciparum

Saito F, Hirayasu K, Satoh T, et al. Immune evasion of Plasmodium falciparum by RIFIN via inhibitory receptors. Nature 2017; 552:101–105.

One of the mechanisms by which the development of autoimmune diseases is guarded against is the surface expression of inhibitory receptors that bind specific self-antigens with the effect of downregulation of autoimmune responses. This self-protective mechanism has been exploited by some viruses that encode molecules that act as ligands capable of binding to such inhibitory receptors, thus allowing them to evade the immune system.

Saito and colleagues set out to see whether Plasmodium falciparum uses a similar method of immune evasion. They began by screening the ability of 13 human inhibitory receptors fused to Fc antibody fragments to bind to infected erythrocytes. Only 1 of the 13, leucocyte immunoglobulin-like receptor B1 (LILRB1), demonstrated such binding. Subsequent studies found that another molecule, leucocyte-associated immunoglobulin-like receptor 1 (LAIR1), also demonstrates binding, although at a low level.

LILRB1 belongs to the LILR family of inhibitory receptors expressed on a variety of immune cells. It recognizes MHC class I molecules. Because erythrocytes do not express the latter and P. falciparum does not possess an MHC class I–like gene, it was concluded that a non-MHC ligand mimicking this molecule must be encoded by the parasite. This ligand proved to be RIFIN. RIFIN, encoded by rif (repetitive interspersed family), is the largest variant surface antigen family in P. falciparum. RIFINs are expressed on the surface of P. falciparum–infected erythrocytes, and their antigenic variability contributes to the ability of the protozoan to evade the immune system. Thus, the binding of RIFNs to LILRB1 receptor molecules on the surface of B cells and NK cells inhibits their activation. In addition, preliminary data indicate that this binding is greater when the red blood cells are obtained from patients with severe malaria rather those with mild malaria, presumably as the result of marked immune cell activation.

This study demonstrates that downregulation of relevant immune cells by the expression of parasite-derived inhibitory molecules on the surface of infected erythrocytes is among the means by which P. falciparum evades the immune response.

Case Vignette: Accelerated Development of a Syphilitic Gumma?

Zhang L, Zhou Y, Chen J, et al. A case of a cerebral syphilitic gumma developed in a few months mimicking a brain tumor in a human immunodeficiency virus–negative patient. Br J Neurosurg 2017; 31:481–483.

Syphilitic gumma is a manifestation of tertiary syphilis that, in most instances, occurs >10 years after primary infection, although this may be accelerated in patients infected with human immunodeficiency virus (HIV). At any rate, syphilitic gumma is currently very rarely encountered.

A 56-year-old, HIV-negative, heterosexual man, who had had a mild headache for 6 months, presented with “extremity” clonus and was found to have a 13 mm × 15 mm mass with surrounding edema in the left parietal lobe on magnetic resonance imaging (MRI). The lesion was excised, and histopathological examination revealed inflammation with a dominance of plasma cells. Spirochetes were not seen on examination of Warthin-Starry silver-stained tissue. Polymerase chain reaction (PCR) testing detected Treponema pallidum nucleic acid.

Several weeks before presentation, the patient had developed a genital ulcer and subsequently underwent serological testing for syphilis and was found to have a negative RPR but a positive TPA. Postoperatively, he was found to have a serum RPR titer of 1:16 and positive TPA. The cerebrospinal fluid TPA was also positive, but silver staining was negative, as was PCR for T. pallidum. Two months after treatment, MRI imaging revealed resolution of the (excised) lesion as well as of edema. At approximately 11 months after presentation, the RPR titer had decreased to 1:4 and was negative several months after that.

Although it can be argued that the initial serological testing was most consistent with previously treated syphilis and this case may not have been an example of accelerated development of a syphilitic gumma, it remains of interest because of its ability to remind clinicians to consider this diagnostic possibility in patients with cerebral masses. A much clearer example of accelerated development of this complication was recently reported, albeit in an HIV-infected patient [1].

Reference