Читать книгу Blood and Marrow Transplantation Long Term Management - Группа авторов - Страница 83

Infections occurring late in allogeneic‐HCT recipients typically have an onset within the first year of transplant, but HCT recipients remain at risk for a long period, especially when being treated with IST for cGVHD. After an allogeneic‐HCT, it may take a few months or up to one year for the immune system to completely reconstitute, thus justifying scheduled re‐vaccinations at regular intervals late after transplant, as indicated per the current immunization guidelines unless treatment for GVHD is ongoing. Owing to both IST and cGVHD, immune recovery can be delayed and a functional immunodeficiency state can persist post‐transplant beyond one year due to impairment of both humoral and cell‐mediated immunity (mainly due to persistent lymphopenia), decreased opsonization, and hyposplenism in certain cases. The risks of acute infections are heightened by mucocutaneous damage, which occurs due to skin, oral, and gastrointestinal (GI) cGVHD, and due to iatrogenic reasons (e.g., intravenous [IV] catheters for extracorporeal photophoresis). Extra care should be taken to examine the catheter sites, and for surveillance of skin or oral mucosal tears due to cGVHD.

Among the late viral infections, Epstein–Barr virus is exceedingly common, but infrequently causes any permanent late sequelae (except posttransplant lymphoproliferative disorder, as discussed later) Varicella zoster virus (VZV) and cytomegalovirus (CMV) are the most common organisms causing complications. The VZV‐mediated infections typically occur during the first 6–12 months post‐HCT (approximately 80% of cases) [12]; the disseminated disease is much more common in allogeneic‐HCTs than in autologous HCTs (45% versus 25%) and the lesions are likely to last longer and heal more slowly than in normal adults [13], necessitating the need for prophylactic therapy with anti‐VZV drugs for a long period even in the absence of cGVHD. Herpes simplex encephalitis, JC/BK infections, hepatitis B and C virus infections and reactivations, and HIV infection are rare late effects and do not necessarily need long‐term surveillance.

Human herpesvirus 6 (HHV‐6) infections occurring after HCT deserve special attention as significant late morbidity and mortality can be associated with this infection [15]. HHV‐6 infection can lead to memory loss, insomnia, confusion, hyperintense signals of the hippocampi on brain magnetic resonance imaging, and temporal lobe seizure activity on electroencephalography [14]. Since similar symptoms may occur in acute meningitis and some cases of calcineurin inhibitor (CNI)‐associated encephalopathy, a high level of suspicion for HHV‐6 encephalitis is required to send the appropriate diagnostic tests for this condition.

Late‐onset fungal infections include candida species, invasive aspergillosis, Fusarium species, and the Zygomycetes. They are more common within a few months of allogeneic‐HCTs and do not require surveillance besides a heightened awareness and prompt diagnostic testing in symptomatic patients for urgent treatment, particularly in high‐risk patients such as cGVHD patients on high‐dose corticosteroids.

Table 6.1 Non‐relapse late and very late effects after allogeneic HCT

Late effect	Incidence	Risk factor	Surveillance/screening	Preventable	Treatable
1. Acute and chronic infections	++	Prolonged immunosuppression, steroids	CT, PCR, serum test	Yes	Yes
2. Cutaneous complications	+++	GVHD	Dermatology exam yearly	No	Yes
3. Oral/dental complications	++	GVHD	Oral exam yearly	No	Yes
4. Hepatic complications	+	HBV, HCV, complementary and alternative medicine, iron overload	T.bil, ALT, US, HBV/HCV viral load, ferritin, T2* MRI, FerriScan, SQUID	No/Yes	Yes/No
5. GI complications	+	GVHD, steroids, mychophenolate mofetil	Endoscopy	No	Yes
6. Genital complications	+	GVHD	Genital exam yearly	No	Yes
7. Renal complications	+	Nephrotoxic medications including CNI	Urine test, serum creatinine	No	Yes/No
8. Ocular complications	++	GVHD, radiation, steroids	Eye exam yearly and when symptomatic [76]	No/Yes	Yes/No
9. Endocrine complications	++	Radiation, steroids, CNI	Thyroid‐stimulating hormone, thyroxine levels, glucose level, HbA1c, glycoalbumin (see reference [77])	No/Yes	Yes
10. Hypogonadism, fertility loss, pregnancy, and lactation issues	+++	Radiation, busulfan	FSH, LH, estrogen, testosterone levels, sperm test	No/Yes	Yes/No
11. Musculoskeletal and bone complications	++	Steroids, GVHD	Dual‐energy X‐ray absorptiometry, MRI	Yes	Yes
12. Pulmonary complications and obliterating bronchiolitis	+	Smoking, radiation, busulfan	Pulmonary function test, high‐resolution chest CT	No	Yes
13. Neurologic complications	++		MRI, neurologic test (see reference [78])	No	Yes/No
14. psychological and social complications	++		psychological test, MRI	No	Yes
15. Sexual dysfunction	+++	GVHD		No	Yes
16. Subsequent hematologic malignancies	+	Patient age, radiation	Blood cell count	No	Yes
17. Cardiovascular complications	+	Thoracic radiation, anthracyclines, cardiovascular risk factors, steroids, genetic polymorphisms	Blood pressure, chest X‐ray, lipid panel, electrocardiogram, echocardiogram, brain natriuretic peptide level	Yes	Yes
18. Subsequent solid malignancies	+	Patient age, radiation, chronic GVHD, long duration of immunosuppression	Recommended screening tests [79]	No	Yes/No

+: <20%, ++:20‐50%; +++: >50%, CNI, calcineurin inhibitor

The usual suspects for late‐onset bacterial infections include staphylococcus species, pseudomonas species, and the encapsulated bacteria [16–18]. The risk of pneumococcal infection is greatest among patients with IgG deficiencies and with severe cGVHD [19], thereby re‐enforcing the need for prophylactic antibiotics (e.g., oral penicillin therapy) and pneumococcal vaccinations. Recently, Clostridium difficile (C. diff) colitis has been found to have a significantly increased incidence in HCT recipients [20], which occurred more frequently in early HCT periods. Interestingly, GI GVHD was found to be strongly associated with an increased risk for recurrent C. diff colitis (OR 4.23, P = 0.02).

HCT recipients residing in certain developing countries may be more susceptible to endemic conditions (e.g., tuberculosis, Chagas disease, and schistosomiasis) which may manifest as late effects post‐allogeneic‐HCT. These endemic infections can have a detrimental effect on QOL of HCT recipients who are already prone to organ dysfunction due to organ involvement; for example, ocular GVHD patients living in areas where Chlamydia trachomatis is endemic are at significantly higher risk of blindness compared with the trachoma‐free geographic locations.

Post‐HCT hypoglobulinemias can be related to cGVHD and are found most commonly in the cases of chronic lymphocytic leukemia. Routine use of antibiotics in asymptomatic hypoglobulinemic patients without evidence of recurrent infections is not indicated.