Ask the Experts - Persistent Fever in Live-Donor Kidney Transplant...
Ask the Experts - Persistent Fever in Live-Donor Kidney Transplant...
A 25-year-old male underwent a living-related-donor kidney transplantation on March 20, 2001. The donor was a single haplotype-matched cousin. The immunosuppression regimen includes cyclosporine, azathioprine (AZA), and prednisolone. The immediate posttransplant course was uneventful and his serum creatinine stabilized at 1.5 mg/dL.
At 9 weeks posttransplant (May 2001), he developed fever with loose motions. Investigations revealed neutropenia, normal urinalysis, and mild increase in serum creatinine, which has remained stable at around 2 mg/dL. The blood cultures are negative and the chest x-ray is normal. In view of fever and neutropenia at this stage of transplant, a diagnosis of cytomegalovirus (CMV) infection was entertained.
Initial CMV IgM and pp65 were negative, but when repeated a week later were positive. Immunosuppression was further reduced (AZA had been stopped earlier when neutropenia developed). Also, ganciclovir was started. Fever persisted and hence, computer tomography scans of the chest and abdomen were performed, which revealed left axillary and multiple mediastinal and intra-abdominal lymph nodes, some of which were necrotic. There was also moderate splenomegaly with 2 hypoechoic lesions and probable 1 small hypoechoic lesion in the transplanted kidney. An axillary lymph node biopsy was performed which revealed infarction. The histopathological specimen stained for AFB was negative. The serum LDH is normal. In spite of 3 weeks of intensive investigations, his fever is persistent. What are we dealing with?
Bharat Shah, MD, DNB
You are most likely dealing with inadequately treated CMV disease or with a disseminated co-opportunistic infection. Certainly, the most common viral infection 9 weeks posttransplant is CMV. In fact, this patient's presentation is classic for CMV disease. Fever, neutropenia, and diarrhea in a transplant recipient is considered CMV disease until proven otherwise. IgM titers are not sensitive, since antibody responses in transplant patients are unreliable. Not surprising, the initial pp65 was negative simply as a technical problem of the assay. Peripheral white blood cells are needed for the immunofluorescence and simply may not have been readily obtained from a specimen in a neutropenic patient. The polymerase chain reaction (PCR) assay for CMV is sufficiently sensitive enough to confirm clinical suspicions.
The real questions are: (1) Why is this patient not improving with ganciclovir therapy?, and (2) Can disseminated CMV lead to the lesions seen in this patient? Reduction of immunosuppression (stopping the AZA) was key. Additionally, the patient requires at least 2-4 weeks of intravenous (IV) ganciclovir therapy. Other adjunctive treatments are controversial and include pooled CMV hyperimmune immunoglobulin. The combination of IV ganciclovir and hyperimmune globulin is generally reserved for the seriously ill patient with tissue-invasive disease (possibly this patient). Frequently, ganciclovir is underdosed and needs to be given at 5 mg/kg every 12 hours, unless the creatinine clearance is severely impaired -- only then should it be dose-adjusted. When ganciclovir is underdosed, it recurs in up to one third of cases. This actually represents untreated disease. CMV could cause disseminated necrosis of lymphoid tissue as has been described for other herpes viruses, and maybe this is what's going on here...but maybe not. CMV disease, in and of itself, can depress host immune responses resulting in additional and coexisting opportunistic infections.
The fact that intensive investigations have been unrevealing usually implies that an atypical pathogen is the causative organism. What atypical pathogens are not revealed by standard microbiological assays? Herpesviruses HHV-6, -7, and -8 are not diagnosed unless specifically tested for. HHV-8 has a propensity to infect lymphoid tissue and shares some homology with Epstein-Barr virus (EBV). Additionally, atypical Mycobacterium infections can be missed by standard assays; however, they should have been detected by the AFB stain. Certainly, Mycobacterium avium-intracellulare, M bovis, or other atypical Mycobacterium infections could cause disseminated lymphoid involvement. Additionally, disseminated toxoplasmosis could cause a scenario similar to that of your patient and might certainly occur in addition to active CMV disease. Other concurrent infections, however, are far more likely to occur. Invasive mycoses can infect transplant patients who are severely immunosuppressed by a combination of antirejection medications and CMV disease. Aspergillus infections have been associated with CMV disease and may actually be a manifestation of the harsh impairment of the patient's immune system. In short, your patient may suffer from a concurrent opportunistic infection as a result of CMV disease in the early posttransplant period. Electron microscopy may help further delineate the responsible pathogen(s).
A 25-year-old male underwent a living-related-donor kidney transplantation on March 20, 2001. The donor was a single haplotype-matched cousin. The immunosuppression regimen includes cyclosporine, azathioprine (AZA), and prednisolone. The immediate posttransplant course was uneventful and his serum creatinine stabilized at 1.5 mg/dL.
At 9 weeks posttransplant (May 2001), he developed fever with loose motions. Investigations revealed neutropenia, normal urinalysis, and mild increase in serum creatinine, which has remained stable at around 2 mg/dL. The blood cultures are negative and the chest x-ray is normal. In view of fever and neutropenia at this stage of transplant, a diagnosis of cytomegalovirus (CMV) infection was entertained.
Initial CMV IgM and pp65 were negative, but when repeated a week later were positive. Immunosuppression was further reduced (AZA had been stopped earlier when neutropenia developed). Also, ganciclovir was started. Fever persisted and hence, computer tomography scans of the chest and abdomen were performed, which revealed left axillary and multiple mediastinal and intra-abdominal lymph nodes, some of which were necrotic. There was also moderate splenomegaly with 2 hypoechoic lesions and probable 1 small hypoechoic lesion in the transplanted kidney. An axillary lymph node biopsy was performed which revealed infarction. The histopathological specimen stained for AFB was negative. The serum LDH is normal. In spite of 3 weeks of intensive investigations, his fever is persistent. What are we dealing with?
Bharat Shah, MD, DNB
You are most likely dealing with inadequately treated CMV disease or with a disseminated co-opportunistic infection. Certainly, the most common viral infection 9 weeks posttransplant is CMV. In fact, this patient's presentation is classic for CMV disease. Fever, neutropenia, and diarrhea in a transplant recipient is considered CMV disease until proven otherwise. IgM titers are not sensitive, since antibody responses in transplant patients are unreliable. Not surprising, the initial pp65 was negative simply as a technical problem of the assay. Peripheral white blood cells are needed for the immunofluorescence and simply may not have been readily obtained from a specimen in a neutropenic patient. The polymerase chain reaction (PCR) assay for CMV is sufficiently sensitive enough to confirm clinical suspicions.
The real questions are: (1) Why is this patient not improving with ganciclovir therapy?, and (2) Can disseminated CMV lead to the lesions seen in this patient? Reduction of immunosuppression (stopping the AZA) was key. Additionally, the patient requires at least 2-4 weeks of intravenous (IV) ganciclovir therapy. Other adjunctive treatments are controversial and include pooled CMV hyperimmune immunoglobulin. The combination of IV ganciclovir and hyperimmune globulin is generally reserved for the seriously ill patient with tissue-invasive disease (possibly this patient). Frequently, ganciclovir is underdosed and needs to be given at 5 mg/kg every 12 hours, unless the creatinine clearance is severely impaired -- only then should it be dose-adjusted. When ganciclovir is underdosed, it recurs in up to one third of cases. This actually represents untreated disease. CMV could cause disseminated necrosis of lymphoid tissue as has been described for other herpes viruses, and maybe this is what's going on here...but maybe not. CMV disease, in and of itself, can depress host immune responses resulting in additional and coexisting opportunistic infections.
The fact that intensive investigations have been unrevealing usually implies that an atypical pathogen is the causative organism. What atypical pathogens are not revealed by standard microbiological assays? Herpesviruses HHV-6, -7, and -8 are not diagnosed unless specifically tested for. HHV-8 has a propensity to infect lymphoid tissue and shares some homology with Epstein-Barr virus (EBV). Additionally, atypical Mycobacterium infections can be missed by standard assays; however, they should have been detected by the AFB stain. Certainly, Mycobacterium avium-intracellulare, M bovis, or other atypical Mycobacterium infections could cause disseminated lymphoid involvement. Additionally, disseminated toxoplasmosis could cause a scenario similar to that of your patient and might certainly occur in addition to active CMV disease. Other concurrent infections, however, are far more likely to occur. Invasive mycoses can infect transplant patients who are severely immunosuppressed by a combination of antirejection medications and CMV disease. Aspergillus infections have been associated with CMV disease and may actually be a manifestation of the harsh impairment of the patient's immune system. In short, your patient may suffer from a concurrent opportunistic infection as a result of CMV disease in the early posttransplant period. Electron microscopy may help further delineate the responsible pathogen(s).
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