Preengraftment — less than three weeks
mmediate postengraftment — three weeks to three months
Late postengraftment — more than three months

Unfortunately, infection is reported as the primary cause of death in 8% of autologous HCT patients and 17% to 20% of allogeneic HCT recipients. Many of these are CMV or varicela-zoster infections. High-dose intravenous acyclovir (500 mg/m2 3 times
daily, from day < 5 until day > 30) followed by oral acyclovir (800 mg 4 times daily for 6 months) has been found to effectively reduce the incidence of CMV disease (52%–59% vs. 61%–75%) and increase overall . patient survival. The Infectious Diseases Society of America (IDSA) issued clinical practice guidelines for preventing opportunistic infections among HCT recipients, published in Biol Blood Marrow Transpant ; 2009 ; 15 : 1143 -1238. IDSA does not recommend open ended acyclovir prophylaxis. It says: “Acyclovir prophylaxis should be offered to all HSV-seropositive allogeneic recipients to prevent HSV reactivation during the early posttransplant…Ganciclovir, high-dose acyclovir, and valacyclovir have all shown efficacy in randomized studies in reducing the risk for CMV infection after HCT period (AI). The standard approach is to begin acyclovir prophylaxis at the start of the conditioning therapy and continue until engraftment occurs or until mucositis resolves, whichever is longer, or approximately 30 days after HCT.” It does appears from its discussion in this section that there may be a benefit for a longer patients who are seropositive for CMV or VZV but the guideline does not define how long and does not specifically recommend it.  NCCN does recommend a year of prophylaxis in CMV or VZV infected patients but otherwise only for 30 days.   American Society of Bone Marrow Transplantation and CDC take the same position in an identical language to the ISDA. 

http://www.idsociety.org/Other_Guidelines/

Michael Angarone et al,Prevention and Early Treatment of Opportunistic Viral Infections in Patients With Leukemia and Allogeneic Stem Cell Transplantation Recipients,  J Natl Compr Canc Netw 2008;6:191-201

Prentice HG, Gluckman E, Powles RL, et al. Impact of long-term acyclovir on cytomegalovirus infection and survival after allogeneic
bone marrow transplantation. European Acyclovir for CMV Prophylaxis Study Group. Lancet 1994;343:749–753.

NCCN, Prevention and Treatment of Cancer Related Infections, INF-3, 2012

Marcie Tomblyn, Tom Chiller, Hermann Einsele, Ronald Gress, Kent Sepkowitz, Jan Storek, John R. Wingard, Jo-Anne H. Young, Michael A. Boeckh
Guidelines for Preventing Infectious Complications among Hematopoietic Cell Transplantation Recipients: A Global Perspective Biol Blood Marrow Transplant 15: 1143-1238 (2009) 2009 American Society for Blood and Marrow Transplantation

For Lay summary see here

Candida spp. and Aspergillus spp. are the most important fungal pathogens contributing to significant morbidity and mortality in immunocompromised patients. Yeast infections are mainly caused by fungi colonizing the gastrointestinal tract, which overgrow under antibacterial treatment and subsequently invade tissue and blood vessels during neutropenia. All allogeneic stem cell recipients should receive anti-fungal prophylaxis; traditionally fluconazole to prevent systemic infection with susceptible yeasts during neutropenia. A recent study published the superiority of itraconazole over fluconazole. However, oral administration of itraconazole is sometimes limited by gastrointestinal side-effects (BI). Voriconazole is a more recent alternative. Overall, antifungal prophylaxis is recommended at least until day +75 post transplant. If immunosuppression is given after day +75, as it would be after an allogeneic transplant,  longer antifungal prophylaxis should be considered. A recent data published in the New England Journal of Medicine showed a clear role of posaconazole in terms of being efficacious and safe and prolonging survival. Voriconazole, being less recent is less studied but is very similar.  Based on NCCN IF-3, it can be approved for 75+ days in total, since he optimal duration of therapy is not known and guidelines that recommend prophylaxis are silent on it duration, except that 75+ days is stated .Voriconazole, being less recent is less studied but is very similar to other drugs of the same class and should be considered to be an accepted option.

A recent review concluded that included evidence-based guidelines recommended posaconazole as an alternative to voriconazole for salvage therapy of IA, and for the primary antifungal prophylaxis against IA in patients with AML or myelodysplastic syndrome, as well as HSCT recipients. The guidelines also suggest posaconazole prophylaxis as an alternative to fluconazole in patients at least 13 years of age with AML or myelodysplastic syndrome during chemotherapy, especially for those considered at higher risk for IA. Posaconazole may be considered in children at least 13 years of age with GVHD after allogeneic HSCT.

A recent review concluded that included evidence-based guidelines recommended posaconazole as an alternative to voriconazole for salvage therapy of IA, and for the primary antifungal prophylaxis against IA in patients with AML or myelodysplastic syndrome, as well as HSCT recipients. The guidelines also suggest posaconazole prophylaxis as an alternative to fluconazole in patients at least 13 years of age with AML or myelodysplastic syndrome during chemotherapy, especially for those considered at higher risk for IA. Posaconazole may be considered in children at least 13 years of age with GVHD after allogeneic HSCT.
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Ye, P., Pei, R., Hu, Y. et al. Posaconazole oral suspension for secondary antifungal prophylaxis in allogeneic stem cell transplantation recipients: a retrospective study. BMC Infect Dis 22, 465 (2022)

Posaconazole for the Prophylaxis and Treatment of Invasive Aspergillosis: A Review of Clinical Effectiveness and Guidelines2022, https://www.ncbi.nlm.nih.gov/books/NBK531401/ Accessed 3/8/2023

Posaconazole Prescribing Information 2023

V. David I.,  Marks et al for the IMPROVIT Study Group Voriconazole versus itraconazole for antifungal prophylaxis following allogeneic haematopoietic stem-cell transplantation British Journal of Haematology Volume 155, Issue 3, pages 318–327, November 2011

W. H. Krüger et al, Antimicrobial prophylaxis in allogeneic bone marrow transplantation. Guidelines of the Infectious Diseases Working Party (AGIHO) of the German Society of Haematology and Oncology Annals of Oncology 2005 16(8):1381-1390;

G. Corrado Prophylaxis and Treatment of Invasive Fungal Diseases in Allogeneic Stem Cell Transplantation: Results of a Consensus Process by Gruppo Italiano Trapianto di Midollo Osseo (GITMO)  Clin Infect Dis. (2009) 49 (8): 1226-1236.

Fleming S1, Yannakou CK, Haeusler GM, Clark J, Grigg A, Heath CH, Bajel A, van Hal SJ, Chen SC, Milliken ST, Morrissey CO, Tam CS, Szer J, Weinkove R, Slavin MA. Consensus guidelines for antifungal prophylaxis in haematological malignancy and haemopoietic stem cell transplantation, Intern Med J. 2014 Dec;44(12b):1283-97.

More recent studies continue to exhibit the same pattern. Torio et al (2011) stated that the Cylex ImmuKnow assay provides a rapid assessment of global immune function in immunocompromised patients by measuring the global immune responses of CD4 T cells from a whole-blood sample. The authors concluded that these findings confirmed that the ImmuKnow assay identified transplant patients at risk for infection.  It may provide information to guide immunosuppressive therapy, but the assay did not seem to have the potential to differentiate subjects experiencing rejection.

De Paolis et al (2011) concluded that this preliminary analysis showed a beneficial capacity of this assay to represent the global depression of the immune system. They did not confirm the predictive value of higher IK values for an increased risk of an acute rejection episode.

Huskey et al (2011) retrospectively analyzed 1,330 ImmuKnow assay values in 583 renal transplant recipients at a single center from 2004 to 2009 and correlated these values with episodes of opportunistic infections (OI) and acute rejection (AR) in the subsequent 90 days. The authors concluded that these findings fail to show an association between single time point ImmuKnow assay values and the subsequent development of an adverse event in the subsequent 90 days.  The optimal use of the ImmuKnow assay in kidney transplantation has yet to be determined. A number of other studies reached similar conclusions.

This test is not currently recommended by any guidelines and should be considered investigational at this time.

Clinical / Medical References:

1. Chon WJ, Brennan DC. Investigational methods in the diagnosis of acute renal allograft rejection. UpToDate [online serial]. Waltham, MA: UpToDate; October 2009.
2. Martinu T, Chen DF, Palmer SM. Acute rejection and humoral sensitization in lung transplant recipients. Proc Am Thorac Soc. 2009;6(1):54-65.
3. Torío A, Fernández E, Montes-Ares O, et al. Lack of association of immune cell function test with rejection in kidney transplantation. Transplant Proc. 2011;43(6):2168-2170.
4. De Paolis P, Favarò A, Piola A, et al. “Immuknow” to measurement of cell-mediated immunity in renal transplant recipients undergoing short-term evaluation. Transplant Proc. 2011;43(4):1013-1016.
5. Huskey J, Gralla J, Wiseman AC. Single time point immune function assay (ImmuKnow) testing does not aid in the prediction of future opportunistic infections or acute rejection. Clin J Am Soc Nephrol. 2011;6(2):423-429.

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