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Give an account of the virological monitoring and antiviral prophylaxis of patients undergoing bone marrow transplantation

 

Bone marrow transplantation is increasingly used as therapy for aplastic anaemia, various haematological malignancies, immunodeficency syndromes and thalessaemia. The process involves the ablation of the host's haematopoietic and immune systems and replacement with those of the marrow donor. In BMT patients, every aspect of the immunological function is depleted. The most commonly used donor is a HLA matched sibling. However, related donors who are not fully matched and fully matched but unrelated donors have also been used. Major complications after transplantation include graft versus host disease (GvHD), toxicity from conditioning and infection. Immunosuppression is given for 100 days or more after allogeneic transplant to prevent GvHD, and patients with GvHD are treated with further immunosuppression. Both GvHD and its treatment increases the risk of infection.

Viral Infections

BMT recipients are at increased risk of developing severe viral infections, in particular from viruses belonging to the herpesvirus family. The following viruses have been recognized in causing disease after BMT.

  1. Herpesviruses - HSV, CMV, VZV, and EBV
  2. Respiratory viruses eg. adenoviruses
  3. Papovaviruses - papilloma, polyomaviruses
  4. Others eg. measles, hepatitis B and C, enteroviruses, diarrhoel viruses, parvovirus

1. Herpesviruses

a. CMV

CMV is the single most important infection in BMT recipients. CMV infection is the single greatest cause of failure of the transplant and occurs 1 to 3 months following transplantation. It occurs in 30 to 40% of seronegative patients given unscreened blood products and up to 80% of seropositive patients who reactivate latent virus (seropositive recipients of graft taken from seronegative donors are at higher risk than those receiving graft from seropositive donors) 15% of infected patients develop CMV pneumonitis which carries a mortality rate of almost 100% in the past. Once pneumonitis ensues, the clinical course is very rapid. Other manifestations of CMV infection include fever, oesophagitis, colitis, hepatitis, encephalitis, retinitis, vasculitis, viraemia and bone marrow failure. The highest mortality occurs 2 to 3 months after the transplant when the patients is out of hospital. There is also a strong association with GvHD but it is uncertain as to which comes first.

b. HSV

HSV infection is common in BMT patients and occurs within the first few weeks following transplant. It is usually due to the reactivation of latent virus and the incidence has been reported to be as high as 75% in BMT patients with previous primary infection. Reactivation may cause severe local or disseminated disease in the form of pneumonitis and oesophagitis.

c. VZV

VZV infection in BMT patients is primarily due to the reactivation of latent virus and occurs in around 35% of patients with previous VZV infection, usually 3 months or more following transplantation. Most patients develop dermatomal zoster and some develop cutaneous dissemination. The mortality rate in the absence of antiviral chemotherapy is 10%.

EBV

Although EBV infection due to reactivating virus is common, most infections are asymptomatic although in a few instances, life threatening lymphoproliferative syndromes, which may or may not respond to acyclovir, have been observed.

2. Respiratory viruses

Adenovirus infections have been reported in up to 8% of BMT recipients. The exact role of adenovirus infections in BMT recipients is still to be evaluated . Infections with other respiratory viruses such influenza A and RSV have also been reported and have caused severe disease in BMT recipients.

3. Papovaviruses

Papillomaviruses may reactivate at a later date following BMT to cause disseminated warts which may progress to squamous carcinomas. Reactivation of JC and BK viruses are common following BMT and is usually asymptomatic. Occasionally, it is associated with acute haemorrhagic cystitis.

Other viruses

Severe enterovirus infections have been recognized in BMT recipients as have severe measles infection. Diarrhoeal viruses such as rotaviruses and enteric adenoviruses do occasionally cause prolonged and severe infections in BMT patients. Persistent and severe parvovirus infection has also been reported. Although BMT recipients who are hepatitis B and C carriers are susceptible to reactivation of active hepatitis B and C infections, the course of the disease is not more severe than in normal individuals.

Virological monitoring

The immune status of the prospective recipient to CMV, HSV, and VZV should be determined before the transplantation. The donor should be screened for CMV, HIV, hepatitis B and hepatitis C. Where possible, the CMV immune status of the donor and recipient should be matched in order to reduce the chance of CMV infection. The immune status of the prospective recipient to measles should also be determined so that inactivated measles vaccine may be given to non-immune individuals. There is no need to determine the immune status to JC and BK viruses. Once the transplant has taken place, the patient should be observed closely for any clinical signs of virus infections such as fever, rash, respiratory and GI symptoms.

Obviously, the main concern is CMV infection. It is of utmost importance to reach a diagnosis of active CMV infection early. Urine, saliva, blood and bronchioalveolar lavage specimens may be used for monitoring purposes. However, the predictive value of a positive isolate from different specimens vary. Blood and BAL are reported to have the highest predictive value for severe CMV disease. although they are not as sensitive as urine and saliva specimens. Saliva specimens have the added advantage of being able to yield HSV in case of active HSV infection. Cell culture is the gold standard for diagnosing CMV infection but its value is limited by the fact that it takes several days for the characteristic CPE to appear. Rapid diagnostic methods include rapid culture methods such as the DEAFF test, detection of CMV antigen from polymorphonuclear cells, and the detection of CMV specific DNA by PCR from white blood cells or serum.

Several protocols have been described for the monitoring of active CMV infection in BMT recipients. Surveillance urine and/or saliva and/or blood specimens are taken either weekly or twice weekly. BALs may be performed routinely in all recipients 1 month after transplant or in the presence of clinical symptoms. It is generally recommended that a positive result from the urine or saliva warrants extra vigilance and due consideration should be given to the relaxation of immunosuppressive therapy. A positive result from the blood or BAL warrants the prophylactic use of ganciclovir or other anti-CMV chemotherapeutic agents.

Routine surveillance for other viral infections are not necessary. Specimens for virology should be taken in case of clinical disease eg. stool specimens for diarrhoea, vesicle fluid in case of vesicular rash, CSF in cases of suspected meningitis etc.

Antiviral prophylaxis

Before the transplant is carried out, one should ensure that the recipient has been immunized against measles, influenza and poliomyelitis. Immunization against VZV using a live VZV vaccine should also be considered in non-immune children. No licensed vaccine is available against CMV. Should one become available, it could be considered for use in both seronegative and seropositive individuals to bolster the immune response against CMV.

Acyclovir is now given routinely as prophylaxis against herpsvirus infections. It is effective against HSV and VZV and is also thought to have valuable effects against CMV and EBV. With the routine prophylactic use of acyclovir, HSV and VZV have ceased to be major problems. It should be given before the transplant and be continued for several months afterwards.  Some centres are advocating the use of ganciclovir as prophylaxis but it is very toxic. Other antiviriral agents such as forscarnet and alpha-interferon are too toxic to be given routinely as pre-transplant prophylaxis. These agents may be used in the post-transplant period should surveillance specimens for CMV turn out to be positive. To conclude, CMV is the major infectious problem in BMT recipients and every effort should be made to monitor the appearance of active CMV infection in BMT recipients so that early intervention may be instituted.
 

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