0
The Cutting Edge |

Cytomegalovirus Ulcer:  Successful Treatment With Valganciclovir FREE

Emily M. Lambert, BA; John Strasswimmer, MD, PhD; Rossitza Lazova, MD; Richard J. Antaya, MD
[+] Author Affiliations

From the Yale University School of Medicine, New Haven, Conn (Ms Lambert and Drs Lazova and Antaya); and Massachusetts General Hospital and Harvard Medical School, Boston (Dr Strasswimmer).


Section Editor: George J. Hruza, MD
Assistant Section Editor: Michael P. Heffernan, MD
Assistant Section Editor: Elaine Siegfried, MD

More Author Information
Arch Dermatol. 2004;140(10):1199-1201. doi:10.1001/archderm.140.10.1199.
Text Size: A A A
Published online

A 47-year-old man with multiple-drug–resistant AIDS was admitted to Yale–New Haven Hospital for evaluation of mental status and neuromotor changes and a 6-week history of a painful, nonhealing, enlarging ulcer on the lower extremity that the patient attributed to minor trauma. The patient had received outpatient wound care and several courses of oral antibiotics, but he was taking neither antiretroviral medications nor prophylaxis for opportunistic infections.

The patient's most recent CD4 cell count was less than 20/µL with a viral load of 715 000 copies/mL. He had a history of successfully treated cytomegalovirus (CMV) retinitis and Pneumocystis carinii pneumonia. On admission, he displayed clinical and radiologic features consistent with cerebral toxoplasmosis. He had no history of diabetes mellitus, peripheral vascular disease, or neuropathic disease.

During his hospital stay, the patient received intravenous and oral antibiotics (ampicillin sodium–sulbactam sodium, aztreonam, and clindamycin) for presumed bacterial infection of the ulcer, and a skin care nurse treated the wound daily with bacitracin zinc and dry dressings. After 4 days in the hospital with no improvement, dermatology consultation was requested.

On physical examination, there was a tender 3.0 × 2.0-cm ulcer on the right lateral part of the heel with surrounding erythema and induration (Figure 1). The border was well demarcated and not elevated, undermined, or scalloped. The base contained granulation tissue and necrotic debris. The patient had no oral, ocular, or anogenital ulcers. The remainder of the lower extremity examination was significant for 1+ pitting ankle edema, adequate capillary refill time, palpable dorsalis pedis pulses, and no evidence of compromised circulation or peripheral neuropathy. The patient also had molluscum contagiosum on his chest.

Place holder to copy figure label and caption
Figure 1.

Ulcer measuring 3.0 × 2.0 cm on the right lateral part of the heel inferior to the malleolus.

Graphic Jump Location

A punch biopsy specimen from the edge of the ulcer showed hyperplastic epidermis and numerous thick-walled blood vessels in the dermis, as well as a perivascular lymphocytic infiltrate. Among normal endothelial cells were many large, irregularly shaped endothelial cells with large basophilic intranuclear inclusions, in some cells surrounded by clear halos. Intracytoplasmic basophilic inclusions were also present (Figure 2).

Place holder to copy figure label and caption
Figure 2.

Two endothelial cells with large basophilic intranuclear inclusions surrounded by clear halos. Intracytoplasmic basophilic inclusions were also present (hematoxylin-eosin, original magnification ×400). Inset, Positive immunohistochemistry stain for cytomegalovirus (original magnification ×400).

Graphic Jump Location

Immunohistochemical studies showed CMV antigen reactivity within the endothelial cells. Direct immunofluorescence examination of ulcer scrapings was negative for herpes simplex virus and varicella-zoster virus antigens. Polymerase chain reaction examination of the ulcer tissue for herpes simplex virus DNA was also negative. Special stains for fungal and bacterial organisms were negative. A biopsy culture from the wound edge failed to demonstrate bacterial, fungal, or mycobacterial growth. A superficial culture of the ulcer yielded mixed flora (Pseudomonas aeruginosa and Enterococcus).

These findings supported the diagnosis of cutaneous CMV infection. An ophthalmologic examination showed no evidence of concomitant retinal disease.

A bone scan demonstrated enhancement in the area of the right calcaneus. Complete blood cell count and electrolyte levels were within reference ranges. Three blood cultures were negative at 5 days. Cytomegalovirus antigenemia was present at greater than 2000 U. Cerebrospinal fluid cultures were negative for acid-fast bacilli, bacteria, and fungi.

Treatment for central nervous system toxoplasmosis with oral pyrimethamine and intravenous clindamycin resulted in improved neurologic status, but the ulcer worsened. Antiretroviral therapy was not initiated because the patient was infected with a multiple-drug–resistant strain of human immunodeficiency virus (HIV). The patient's discharge to home hospice care was planned with a regimen of intravenous clindamycin and oral leucovorin calcium treatment for the cerebral toxoplasmosis and intravenous aztreonam to treat the possible osteomyelitis. Oral dapsone and valganciclovir hydrochloride plus nystatin oral rinse were indicated for prophylaxis against opportunistic infections.

Cutaneous CMV infection has been successfully treated with intravenous ganciclovir and foscarnet sodium.13 Although induction therapy followed by maintenance inactivates the virus, in the absence of good immune system function, long-term treatment is necessary.4 The requirement for extended intravenous administration of antiviral medications would have severely impacted this patient's quality of life, increased his risk of infection, and required expensive nursing care.

A new oral antiviral medication, valganciclovir, was proposed as an alternative to prolonged intravenous ganciclovir or foscarnet.5 Valganciclovir hydrochloride (Valcyte; Roche Laboratories Inc, Nutley, NJ), 900 mg orally, was administered twice daily for 3 weeks. After 2 weeks of therapy, the CMV antigenemia decreased to below the limits of detection and the dosage of valganciclovir was decreased to once daily for maintenance. Because of the concern of possible concomitant osteomyelitis, the patient also received a 6-week course of aztreonam. There was marked improvement of the swelling of the extremity and subsequent healing of the ulcer. Six weeks after the initiation of valganciclovir therapy, the ulcer was mostly resolved, and the patient was able to walk again (Figure 3).

Place holder to copy figure label and caption
Figure 3.

The ulcer 6 weeks after the initiation of valganciclovir hydrochloride therapy.

Graphic Jump Location

Treatment of the cerebral toxoplasmosis resulted in improved cognitive function. Because the patient had a highly resistant HIV genotype and had not tolerated antiretroviral therapy well in the past, he opted to forgo HIV treatment. The patient died in hospice 10 weeks after our initial consultation.

Cytomegalovirus is a common opportunistic agent in immunocompromised hosts with AIDS6,7 and solid organ810 and hematologic11 transplantation and in the setting of iatrogenic suppression in the treatment of cutaneous lupus erythematosus.12

Cytomegalovirus is a member of the herpes family of DNA viruses. Herpesviruses are capable of latency after infection with an acute disease followed by an asymptomatic, quiescent state. Eighty percent of adults have antibodies against CMV. Infection with CMV in most immunocompetent hosts is asymptomatic but can present as a mononucleosislike syndrome.13 A compromise of the host's immune system can lead to reactivation of latent viruses and viral proliferation.

Cytomegalovirus is the virus most frequently isolated from people with AIDS. Ninety percent of patients with AIDS are infected with CMV, and disseminated CMV is found during autopsy in 93% of patients with AIDS. Reactivation of latent CMV infection causes significant morbidity and mortality in immunocompromised patients. In an AIDS-infected host, CMV causes a variety of conditions, including pneumonia, encephalitis, gastrointestinal ulcers, hepatitis, retinitis, and disseminated disease. Cytomegalovirus retinitis is the most common manifestation of CMV in an HIV-positive host.14

There are infrequent reports in the literature of cutaneous CMV infections. This may be because cutaneous CMV infections are uncommon or because making a diagnosis of CMV is difficult as a result of its multiple clinical presentations and subtle histopathological findings. Skin lesions of CMV characteristically affect immunocompromised hosts, presenting as maculopapular rashes, urticarial eruptions, scarlatiniform eruptions, cutaneous ulcerations, oral ulcerations, crusted papules, nodules, morbilliform eruptions, verrucous lesions, perifollicular papulopustules, urticaria, or vesiculobullous eruptions.15 Cutaneous CMV lesions often herald disseminated infection16 and are associated with a mortality of 85% within 6 months.10

There is some controversy surrounding the pathogenic role of CMV in cutaneous lesions. It has been argued that CMV found in ulcerative lesions could be the result of a hematogenously disseminated infection, reactivation within the endothelial cells, or autoinoculation through urine, feces, or saliva shedding because the majority of CMV ulcers are found in the genital and perianal regions.17 Other infectious agents are frequently cultured from lesions attributed to CMV. Cytomegalovirus has been found unexpectedly in healthy skin. Spontaneous healing of CMV-positive lesions may occur. We believe that CMV did play a pathogenic role in this patient's ulcer: no other microorganisms were detected, there was minimal risk of autoinoculation at this site, and treatment with a specific antiviral agent yielded rapid and dramatic clinical improvement, while there was no improvement in his HIV infection.

Ganciclovir and foscarnet have been efficacious in the treatment of cutaneous CMV.3,18 Valganciclovir was approved by the Food and Drug Administration in 2001 for the treatment of CMV retinitis in immunocompromised hosts. Sixty percent of oral valganciclovir is absorbed vs 6% to 9% of oral ganciclovir. Plasma levels of oral valganciclovir are comparable with those of intravenous ganciclovir,19 as are efficacy and adverse effects.20

This is, to our knowledge, the first report of successful treatment of cutaneous CMV infection with an oral medication. Moreover, this therapy was effective despite profound immunocompromise. This therapeutic option is extremely valuable because valganciclovir does not require an indwelling catheter and removes all of the complications associated with these devices, a risk reduction especially important in an immunocompromised patient population.

Submissions

Clinicians, local and regional societies, residents, and fellows are invited to submit cases of challenges in management and therapeutics to this section. Cases should follow the established pattern. Submit 4 double-spaced copies of the manuscript with right margins nonjustified and 4 sets of the illustrations. Photomicrographs and illustrations must be clear and submitted as positive color transparencies (35-mm slides) or black-and-white prints. Do not submit color prints unless accompanied by original transparencies. Material should be accompanied by the required copyright transfer statement, as noted in "Instructions for Authors." Material for this section should be submitted to George J. Hruza, MD, Laser and Dermatologic Surgery Center Inc, 14377 Woodlake Dr, Suite 111, St Louis, MO 63017.

Correspondence: Richard J. Antaya, MD, Department of Dermatology, Yale University School of Medicine, PO Box 208059, 333 Cedar St, LCI 501, New Haven, CT 06520 (richard.antaya@yale.edu).

Accepted for publication October 10, 2003.

The authors have no relevant financial interest in this article.

Colsky  ASJegasothy  SMLeonardi  CKirsner  RSKerdel  FA Diagnosis and treatment of a case of cutaneous cytomegalovirus infection with a dramatic clinical presentation J Am Acad Dermatol. 1998;38349- 351
PubMed
Horn  TDHood  AF Clinically occult cytomegalovirus present in skin biopsy specimens in immunosuppressed hosts J Am Acad Dermatol. 1989;21781- 784
PubMed
Myers  JD Management of cytomegalovirus infection Am J Med. 1988;85102- 106
PubMed
Martin  DFSierra-Madero  JWalmsley  S  et al.  A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis N Engl J Med. 2002;3461119- 1126[published correction appears in N Engl J Med. 2002;347:862]
PubMed
Not Available, Valganciclovir hydrochloride Am J Health Syst Pharm. 2001;582246- 2247
PubMed
Macher  AMReichert  CMStraus  SE  et al.  Death in the AIDS patient: role of cytomegalovirus [letter] N Engl J Med. 1983;3091454
PubMed
Salmon-Ceron  D Cytomegalovirus infection: the point in 2001 HIV Med. 2001;2255- 259
PubMed
Wong  JMcCracken  GRonan  SAronson  I Coexistent cutaneous Aspergillus and cytomegalovirus infection in a liver transplant recipient J Am Acad Dermatol. 2001;44370- 372
PubMed
Patterson  JWBroecker  AHKornstein  MJMills  AS Cutaneous cytomegalovirus infection in a liver transplant patient: diagnosis by in situ DNA hybridization Am J Dermatopathol. 1988;10524- 530
PubMed
Lee  JY Cytomegalovirus infection involving the skin in immunocompromised hosts: a clinicopathologic study Am J Clin Pathol. 1989;9296- 100
PubMed
Zaia  JAForman  SJ Cytomegalovirus infection in the bone marrow transplant recipient Infect Dis Clin North Am. 1995;9879- 900
PubMed
Sekigawa  INawata  MSeta  NYamada  MIida  NHashimoto  H Cytomegalovirus infection in patients with systemic lupus erythematosus Clin Exp Rheumatol. 2002;20559- 564
PubMed
Cohen  JICorey  GR Cytomegalovirus infection in the normal host Medicine (Baltimore). 1985;64100- 114
PubMed
Toome  BKBowers  KEScott  GA Diagnosis of cutaneous cytomegalovirus infection: a review and report of a case J Am Acad Dermatol. 1991;24860- 867
PubMed
Drago  FAragone  MGLugani  CRebora  A Cytomegalovirus infection in normal and immunocompromised humans: a review Dermatology. 2000;200189- 195
PubMed
Pariser  RJ Histologically specific skin lesions in disseminated cytomegalovirus infection J Am Acad Dermatol. 1983;9937- 946
PubMed
Dauden  EFernandez-Buezo  GFraga  JCardenoso  LGarcia-Diez  A Mucocutaneous presence of cytomegalovirus associated with human immunodeficiency virus infection: discussion regarding its pathogenetic role Arch Dermatol. 2001;137443- 448
PubMed
Collaborative DHPG Treatment Study Group, Treatment of serious cytomegalovirus infections with 9-(1,3-dihydroxy-2-propoxymethyl)guanine in patients with AIDS and other immunodeficiencies N Engl J Med. 1986;314801- 805
PubMed
Jung  DDorr  A Single-dose pharmacokinetics of valganciclovir in HIV- and CMV-seropositive subjects J Clin Pharmacol. 1999;39800- 804
PubMed
Not Available, Valcyte, Valganciclovir [package insert]  Nutley, NJ Roche Laboratories Inc March2001;

Figures

Place holder to copy figure label and caption
Figure 1.

Ulcer measuring 3.0 × 2.0 cm on the right lateral part of the heel inferior to the malleolus.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.

Two endothelial cells with large basophilic intranuclear inclusions surrounded by clear halos. Intracytoplasmic basophilic inclusions were also present (hematoxylin-eosin, original magnification ×400). Inset, Positive immunohistochemistry stain for cytomegalovirus (original magnification ×400).

Graphic Jump Location
Place holder to copy figure label and caption
Figure 3.

The ulcer 6 weeks after the initiation of valganciclovir hydrochloride therapy.

Graphic Jump Location

Tables

References

Colsky  ASJegasothy  SMLeonardi  CKirsner  RSKerdel  FA Diagnosis and treatment of a case of cutaneous cytomegalovirus infection with a dramatic clinical presentation J Am Acad Dermatol. 1998;38349- 351
PubMed
Horn  TDHood  AF Clinically occult cytomegalovirus present in skin biopsy specimens in immunosuppressed hosts J Am Acad Dermatol. 1989;21781- 784
PubMed
Myers  JD Management of cytomegalovirus infection Am J Med. 1988;85102- 106
PubMed
Martin  DFSierra-Madero  JWalmsley  S  et al.  A controlled trial of valganciclovir as induction therapy for cytomegalovirus retinitis N Engl J Med. 2002;3461119- 1126[published correction appears in N Engl J Med. 2002;347:862]
PubMed
Not Available, Valganciclovir hydrochloride Am J Health Syst Pharm. 2001;582246- 2247
PubMed
Macher  AMReichert  CMStraus  SE  et al.  Death in the AIDS patient: role of cytomegalovirus [letter] N Engl J Med. 1983;3091454
PubMed
Salmon-Ceron  D Cytomegalovirus infection: the point in 2001 HIV Med. 2001;2255- 259
PubMed
Wong  JMcCracken  GRonan  SAronson  I Coexistent cutaneous Aspergillus and cytomegalovirus infection in a liver transplant recipient J Am Acad Dermatol. 2001;44370- 372
PubMed
Patterson  JWBroecker  AHKornstein  MJMills  AS Cutaneous cytomegalovirus infection in a liver transplant patient: diagnosis by in situ DNA hybridization Am J Dermatopathol. 1988;10524- 530
PubMed
Lee  JY Cytomegalovirus infection involving the skin in immunocompromised hosts: a clinicopathologic study Am J Clin Pathol. 1989;9296- 100
PubMed
Zaia  JAForman  SJ Cytomegalovirus infection in the bone marrow transplant recipient Infect Dis Clin North Am. 1995;9879- 900
PubMed
Sekigawa  INawata  MSeta  NYamada  MIida  NHashimoto  H Cytomegalovirus infection in patients with systemic lupus erythematosus Clin Exp Rheumatol. 2002;20559- 564
PubMed
Cohen  JICorey  GR Cytomegalovirus infection in the normal host Medicine (Baltimore). 1985;64100- 114
PubMed
Toome  BKBowers  KEScott  GA Diagnosis of cutaneous cytomegalovirus infection: a review and report of a case J Am Acad Dermatol. 1991;24860- 867
PubMed
Drago  FAragone  MGLugani  CRebora  A Cytomegalovirus infection in normal and immunocompromised humans: a review Dermatology. 2000;200189- 195
PubMed
Pariser  RJ Histologically specific skin lesions in disseminated cytomegalovirus infection J Am Acad Dermatol. 1983;9937- 946
PubMed
Dauden  EFernandez-Buezo  GFraga  JCardenoso  LGarcia-Diez  A Mucocutaneous presence of cytomegalovirus associated with human immunodeficiency virus infection: discussion regarding its pathogenetic role Arch Dermatol. 2001;137443- 448
PubMed
Collaborative DHPG Treatment Study Group, Treatment of serious cytomegalovirus infections with 9-(1,3-dihydroxy-2-propoxymethyl)guanine in patients with AIDS and other immunodeficiencies N Engl J Med. 1986;314801- 805
PubMed
Jung  DDorr  A Single-dose pharmacokinetics of valganciclovir in HIV- and CMV-seropositive subjects J Clin Pharmacol. 1999;39800- 804
PubMed
Not Available, Valcyte, Valganciclovir [package insert]  Nutley, NJ Roche Laboratories Inc March2001;

Correspondence

CME
Meets CME requirements for:
Browse CME for all U.S. States
Accreditation Information
The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians. The AMA designates this journal-based CME activity for a maximum of 1 AMA PRA Category 1 CreditTM per course. Physicians should claim only the credit commensurate with the extent of their participation in the activity. Physicians who complete the CME course and score at least 80% correct on the quiz are eligible for AMA PRA Category 1 CreditTM.
Note: You must get at least of the answers correct to pass this quiz.
You have not filled in all the answers to complete this quiz
The following questions were not answered:
Sorry, you have unsuccessfully completed this CME quiz with a score of
The following questions were not answered correctly:
Commitment to Change (optional):
Indicate what change(s) you will implement in your practice, if any, based on this CME course.
Your quiz results:
The filled radio buttons indicate your responses. The preferred responses are highlighted
For CME Course: A Proposed Model for Initial Assessment and Management of Acute Heart Failure Syndromes
Indicate what changes(s) you will implement in your practice, if any, based on this CME course.
NOTE:
Citing articles are presented as examples only. In non-demo SCM6 implementation, integration with CrossRef’s "Cited By" API will populate this tab (http://www.crossref.org/citedby.html).
Submit a Comment

Multimedia

Some tools below are only available to our subscribers or users with an online account.

Related Content

Customize your page view by dragging & repositioning the boxes below.

Articles Related By Topic
Related Topics
PubMed Articles
JAMAevidence.com