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January 6, 2015 Issue

Clinical Practice Points

Medical Knowledge

Valganciclovir for the Prevention of Complications of Late Cytomegalovirus Infection After Allogeneic Hematopoietic Cell Transplantation

Cytomegalovirus (CMV) disease may complicate hematopoietic cell transplantation. This multicenter trial found no difference between valganciclovir prophylaxis and polymerase chain reaction–guided preemptive therapy in the occurrence of death, CMV disease, or other infections and concluded that both strategies are effective in preventing CMV disease in the setting of hematopoietic cell transplantation.

Use this study to:

  • Start a teaching session with a multiple-choice question. We’ve provided one below.
  • Review the risks for and clinical manifestations of CMV infection in immunocompromised patients. How is it treated? Is CMV a problem for immunocompetent patients? What about during pregnancy?
  • Invite a member of your institution’s infectious disease and oncology divisions to discuss the rationale behind bone marrow transplantation, the mechanisms by which they are thought to work in different diseases, and the infectious risks.
  • How does your institution approach the prevention of CMV infection in patients undergoing bone marrow transplantation?

Medical Knowledge
Patient Care

Multitarget Therapy for Induction Treatment of Lupus Nephritis. A Randomized Trial.

The current single-drug induction regimens for lupus nephritis are associated with low rates of complete remission. This multicenter trial found that a multidrug regimen targeting different components of the immune system resulted in higher rates of remission among patients with lupus nephritis. Although adverse events resulted in more patients withdrawing from the multidrug group than the standard treatment group, the overall rate of adverse events was similar.

Use this study to:

  • Review with your learners how the diagnosis of lupus is made and what evaluation of renal function is required. Use a recent In the Clinic: Systemic Lupus Erythematosus to prepare for teaching.
  • Ask your learners what the differential diagnosis is of acute glomerulonephritis. Use the information in ACP Smart Medicine: Acute Glomerulonephritis, including an image of an erythrocyte cast in the urine. Review the histologic changes before and after therapy of a patient who achieved complete remission, shown in the appendix to this article.
  • Invite a rheumatologist or nephrologist to discuss how s/he approaches induction therapy for lupus nephritis. How is response (complete or partial remission) assessed? When? This study assessed outcomes at 24 weeks. Is that sufficient to alter the approach to therapy? Why or why not?
  • Take a moment to reflect on how medical practice progresses. During ACP’s Centennial year, articles from the Annals archive are highlighted. Noted in this issue is a trial reported in 1972 when new immunosuppressive drugs were being added to prednisone, the only minimally effective treatment for SLE since the 1940s. Although this trial found no benefit from the addition of azathioprine to prednisone, it was randomized (an improvement over prior studies) and developed a scoring system to assess renal function and biopsy results. Why were both of these important advances, even if the results of this lone trial did not identify a means to improve care?

Medical Knowledge
Patient Care

D-Dimer Testing to Select Patients With a First Unprovoked Venous Thromboembolism Who Can Stop Anticoagulants

Normal D-dimer levels after withdrawal of anticoagulant therapy are associated with a reduced risk for recurrence in patients with unprovoked venous thromboembolism (VTE) and may justify stopping treatment. The findings of this prospective cohort study of patients with a first unprovoked VTE and normal posttreatment D-dimer levels suggest that anticoagulation should be continued indefinitely in men and that the situation is more complicated in women.

Use this study to:

  • Discuss the therapeutic plans for several outpatients in your residents’ practices. Ask each to think of a patient they follow who is on anticoagulation therapy following a VTE. Summarize each in a sentence or two—noting whether there were known risks for VTE. How long do they plan anticoagulation for each? Why?
  • Ask what factors are considered when making recommendations for the duration of anticoagulation following VTE.
  • Ask if any of your learners has considered or used a D-dimer measurement following the discontinuation of anticoagulation therapy to help decide whether to continue therapy. How might the results of this cohort study influence their approach? The authors offer their interpretation in the paper’s discussion.

Medical Knowledge
Patient Care
Interpersonal and Communication Skills
Systems-based Practice
In the Clinic:

Rotator Cuff Disease

The monthly prevalence of shoulder pain in the general population is reported to be between 18% and 31%! Are your learners prepared to evaluate and manage this common, and frequently difficult, problem?

Use this review to:

  • Review the anatomy of the shoulder.
  • Ask what symptoms suggest rotator cuff disease. What findings on physical examination are helpful? Use the table for a concise summary of tests and what their results indicate. Examine each other’s shoulders and/or those of patients with pain.
  • What are possible causes of shoulder pain? Tables 2 and 3 will help generate a list of important considerations.
  • When are imaging tests indicated? When should a patient be referred to a surgical or nonsurgical consultant? How should rotator cuff disease be managed? Can it be prevented?
  • Use the multiple-choice questions provided at the end to introduce and answer these and other questions addressed in this review. Then, log on and claim CME credit for yourself by entering your answers.
  • Download the ready-to-use slides to help you prepare for a teaching session.


A 26-year-old man is evaluated for a 3-day history of fever, lower abdominal pain, tenesmus, hematochezia, and watery diarrhea. Seven months ago, he underwent a cadaveric kidney transplantation. At the time of transplantation, the transplant donor was seropositive for cytomegalovirus, and the patient was seronegative for this virus. Current medications are tacrolimus, mycophenolate mofetil, prednisone, and trimethoprim-sulfamethoxazole. Valganciclovir was discontinued 1 month ago after 6 months of prophylaxis as per standard protocol.

On physical examination, temperature is 38.8 °C (101.8 °F), blood pressure is 100/70 mm Hg, pulse rate is 104/min, and respiration rate is 18/min. BMI is 24. Cardiopulmonary examination is normal. Abdominal examination reveals increased bowel sounds but no tenderness to palpation. There is no organomegaly.

Laboratory studies:

Leukocyte count 2100/µL (2.1 × 109/L)
Alanine aminotransferase 72 units/L
Aspartate aminotransferase 60 units/L
Serum creatinine 1.4 mg/dL (124 µmol/L)

Chest radiograph is normal.

Which of the following is the most likely diagnosis?

A. Clostridium difficile infection
B. Cytomegalovirus infection
C. Mycophenolate mofetil toxicity
D. Tacrolimus toxicity

Correct Answer
B. Cytomegalovirus infection

Key Point
Cytomegalovirus infection is particularly common in kidney transplant recipients and may manifest as fever, leukopenia, and diarrhea.

Educational Objective
Diagnose cytomegalovirus infection in a kidney transplant recipient.

The most likely diagnosis is cytomegalovirus (CMV) infection. Despite advances in immunosuppressive therapy and infection prophylaxis, more than 50% of kidney transplant recipients develop at least one infection during the first year after transplantation. CMV infection is particularly common in these patients. CMV infection is often suspected when patients have leukopenia and fevers during the posttransplant period. Viremia is best detected by polymerase chain reaction (PCR), a fast, sensitive, and reliable technique compared with serology, culture, or early antigen or CMV antigenemia detection. CMV infection can result in CMV disease, with organ involvement manifesting as retinitis, pneumonia, encephalitis, hepatitis, and gastrointestinal tract ulceration.

This patient underwent kidney transplantation 7 months ago and discontinued his CMV prophylaxis therapy 1 month ago as per standard protocol. Kidney transplantation from a donor who is seropositive for CMV to a recipient who is seronegative for this virus places the recipient at high risk for developing this condition. Furthermore, this patient's fever, leukopenia, and diarrhea are consistent with CMV infection, and his elevated liver chemistry studies raise suspicion for CMV-related hepatitis. Diagnosis of CMV infection is confirmed with a positive serum PCR test for viremia, and disease is confirmed by the presence of mucosal ulcers or erosion and CMV inclusion bodies seen on a biopsy specimen from the wall of the bowel obtained during colonoscopy.

Clostridium difficile infection may cause diarrhea and fever but does not explain this patient's leukopenia or elevated aminotransferase levels.

Mycophenolate mofetil can cause diarrhea and leukopenia but is rarely associated with elevated liver chemistry studies and does not explain this patient's fever. In addition, toxicity associated with mycophenolate mofetil usually occurs after a recent dosage change.

Tacrolimus toxicity can cause diarrhea but does not manifest as fever, leukopenia, or abnormal findings on liver chemistry studies.

Helanterä I, Lautenschlager I, Koskinen P. The risk of cytomegalovirus recurrence after kidney transplantation. Transpl Int. 2011;24(12):1170-1178. PMID: 21902725

The MKSAP question included in the December 16, 2014 issue of Annals for Educators involved an 18 year old woman with a history consistent with disseminated gonococcal infection, including a 3-day history of fever, a painful and swollen elbow and a rash. Although the correct answer regarding making a definitive diagnosis with culture of the cervix, urethra or rectum was provided, a technical error resulted in the presentation of an incorrect explanation. We apologize for the error and thank our reader who alerted us to it. The correct explanation is:

This patient most likely has disseminated gonococcal infection (DGI). DGI may cause septic or sterile immune-mediated arthritis and tenosynovitis and frequently involves the knees, hips, and wrists but not the spine. Dermatitis associated with sparse peripheral necrotic pustules also is common. A characteristic prodrome of migratory arthralgia and tenosynovitis may precede the settling of the synovitis in one or several joints.

Genitourinary symptoms associated with DGI usually are absent in women, and genital infection in women may have occurred long before systemic dissemination. Rectal and pharyngeal Neisseria gonorrhoeae infection are commonly asymptomatic. In persons in whom DGI is clinically suspected, evaluation of the exposed mucosal sites including culture or nucleic acid amplication testing (NAAT) of the cervix, rectum, or pharynx, is indicated. The sensitivity of NAATs for the detection of gonorrhea is superior to culture at nongenital anatomic sites but can vary by NAAT type with gonorrhea. Blood cultures, aspiration of joint fluid or peripheral lesions can also be performed, but the diagnostic yield at these sites is lower than at mucosal sites.

Prompt evaluation for additional sexually transmitted diseases, including Chlamydia, syphilis and HIV, is indicated. Gonococcal infection is frequently asymptomatic in sex partners of those with DGI. Sexual partners of patients with DGI also should be evaluated and treated.

This question is derived from MKSAP® 16, the Medical Knowledge Self-Assessment Program.

From the Editors of Annals of Internal Medicine and Education Guest Editor, Gretchen Diemer, MD, FACP, Program Director in Internal Medicine, Thomas Jefferson University.


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