Outline the clinical features, diagnostic tests and initial drug treatment of cytomegalovirus (CMV) infection in an immunosuppressed patient.

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College answer

Clinical features (4 marks)

CMV infection can range from asymptomatic viraemia to CMV syndrome and tissue invasive disease.

CMV syndrome is defined as the presence of detectable viral replication in blood accompanied by attributable symptoms and signs: fever, malaise, arthralgia, leukopenia, thrombocytopenia.

Tissue-invasive CMV disease has clinical symptoms and signs of end-organ disease:

GI – diarrhoea, fever, abdominal pain, bloody stool

Hepatic – LFT abnormalities Neurological – Encephalitis, GBS Pneumonitis

Retinitis

Can reactivate in critical illness.

Diagnosis (4 marks)

Serology IgM and IgG – can indicate past infection

PCR CMV DNA – blood / CSF/BAL – copies per ml / standard units / ml

Biopsy if tissue invasive disease with typical histology cellular and nuclear enlargement, inclusion bodies

Viral cultures in past – slow, high cost, long turnaround

Treatment (2 marks)

Stop/reduce immunosuppressive drugs if possible Ganciclovir

Valganciclovir

Foscarnet (IV), Cidofovir (IV) Consider IVIG or CMV IG

Examiners Comments:

Overall poor knowledge of this topic. Many candidates gave a list of clinical syndromes associated with CMV without detail of the clinical features as required by the stem. Many of the diagnostic tests discussed were generic tests of potentially affected end organ function, rather than tests that would secure the specific diagnosis. The stem asked specifically for drug treatment. Some candidates gave details of supportive therapy and resuscitation that were not necessary.
 

Discussion

Clinical manifestations of CMV:

Immunocompetent host

  • Pneumonia
  • Colitis
  • Bone marrow suppression
  • CMV mononucleosis
  • LFT derangement

Immunocompromised host

  • Pneumonia
  • Colitis
  • Oesophagitis
  • Retinitis and uveitis
  • Encephalitis
  • Meningitis
  • Pericarditis and myocarditis
  • Hepatitis
  • Guillain-Barre syndrome

CMV syndrome is defined as viraemia plus any two of the following:

  • Fever ≥38°C for at least 2 days.
  • New or increased malaise or  fatigue 
  • Leukopenia or neutropenia 
  • >5% atypical lymphocytes
  • Thrombocytopenia 
  • Elevation of aminotransferases

This definition is based on Ljungman et al (2016).

Diagnosis of CMV

  • Positive CMV antibodies (IgM or IgG) - sensitive for recent or acute infection
    • However, this is obviously invalidated by IVIg infusion, plasmapheresis, and such other.
  • Antigen assay (for pp65 antigen) is cheap and used to be the standard, but it requires a few neutrophils and cannot be performed in severe neutropenia. The blood needs to be fresh; one is better off sending this test during working hours.
  • Qualitative PCR for CMV DNA- very sensitive for the presence of CMV, but they do not distingusih between active and latent infection.
  • Quantitative PCR for CMV DNA - ideal test, as it provides a quantitative assessment of viral load, and allows the monitoring of therapy. The WHO have set up an international standard for this technique.
  • Tissue histology: one cannot always have access to the tissue, but it does allow the identification of these characteristic cytomegalic cells.
  • Viral cultures: These take some time; in vivo CMV is cultured in fibroblasts.

Management:

Extensive literature exists concerning CMV in the immunocompromised:

  • Ganciclovir is first-line: a selective inhibitor of CMV DNA polymerase. Much more activity against CMV than aciclovir.
    • Valganciclovir usually follows: it is the orally bioavailable pro-drug.
    • Ganciclovir-soaked pellets can be sutured into the eye to treat retinitis
  • Foscarnet is second-line: it is sodium phosphonoformate, and it also inhibits CMV DNA polymerase.
    • Unfortunately, it is hideously nephrotoxic and neurotoxic.
  • Cidofovir is an alternative second-line: a nucleotide analogue, it also selectively inhibits CMV DNA polymerase.
    • It is also nephrotoxic
    • The major approved indication is the management of CMV retinitis
  • CMV immunoglobulin is specific antibodies to CMV from immune hosts.

References

References

Gandhi, Maher K., and Rajiv Khanna. "Human cytomegalovirus: clinical aspects, immune regulation, and emerging treatments." The Lancet infectious diseases 4.12 (2004): 725-738.

Tejedor Cerdena, María Auxiliadora, et al. "Cytomegalovirus ileitis in an immunocompetent patient." Rev Esp Enferm Dig 103 (2011): 154-6.

Grilli, Elisabetta, et al. "Cytomegalovirus pneumonia in immunocompetent host: case report and literature review." Journal of Clinical Virology 55.4 (2012): 356-359.

Limaye, Ajit P., et al. "Cytomegalovirus reactivation in critically ill immunocompetent patients." Jama 300.4 (2008): 413-422.

Osawa, Ryosuke, and Nina Singh. "Cytomegalovirus infection in critically ill patients: a systematic review." Critical care 13.3 (2009): R68.

Jain, Manisha, Shalini Duggal, and Tulsi Das Chugh. "Cytomegalovirus infection in non-immunosuppressed critically ill patients." The Journal of Infection in Developing Countries 5.08 (2011): 571-579.

Chou, Suowen. "Newer methods for diagnosis of cytomegalovirus infection." Review of Infectious Diseases 12.Supplement 7 (1990): S727-S736.

Razonable, Raymund R., and Randall T. Hayden. "Clinical utility of viral load in management of cytomegalovirus infection after solid organ transplantation."Clinical microbiology reviews 26.4 (2013): 703-727.

Vancikova, Z., and P. Dvorak. "Cytomegalovirus infection in immunocompetent and immunocompromised individuals--a review." Current drug targets. Immune, endocrine and metabolic disorders 1.2 (2001): 179-187.

Eddleston, M., et al. "Severe cytomegalovirus infection in immunocompetent patients." Clinical infectious diseases 24.1 (1997): 52-56.

Andrews, Peter A., Vincent C. Emery, and Chas Newstead. "Summary of the British Transplantation Society guidelines for the prevention and management of CMV disease after solid organ transplantation." Transplantation 92.11 (2011): 1181-1187.

Kotton, Camille N., et al. "Updated international consensus guidelines on the management of cytomegalovirus in solid-organ transplantation." Transplantation96.4 (2013): 333-360.

Jacobson, Mark A. "Review of the toxicities of foscarnet." JAIDS Journal of Acquired Immune Deficiency Syndromes 5 (1992): S11-17.

Lalezari, Jacob P., et al. "Randomized, controlled study of the safety and efficacy of intravenous cidofovir for the treatment of relapsing cytomegalovirus retinitis in patients with AIDS." JAIDS Journal of Acquired Immune Deficiency Syndromes 17.4 (1998): 339-344.

Boeckh, Michael. "Complications, diagnosis, management, and prevention of CMV infections: current and future." ASH Education Program Book 2011.1 (2011): 305-309.

Kotton, C. N. "CMV: prevention, diagnosis and therapy." American Journal of Transplantation 13.s3 (2013): 24-40.

Fryer, J. F., et al. "Collaborative study to evaluate the proposed 1st WHO international standard for human cytomegalovirus (HCMV) for nucleic acid amplification (NAT)-based assays WHO/BS/10.2138." World Health Organiztion, Geneva, Switzerland (2010).

Ljungman, P., et al. "Use of intravenous immune globulin in addition to antiviral therapy in the treatment of CMV gastrointestinal disease in allogeneic bone marrow transplant patients: a report from the European Group for Blood and Marrow Transplantation (EBMT). Infectious Diseases Working Party of the EBMT." Bone marrow transplantation 21.5 (1998): 473-476.

Erard, V., et al. "Cytomegalovirus pneumonia after hematopoietic cell transplantation: outcomes and factors associated with mortality." Interscience Conference on Antimicrobial Agents and Chemotherapy. Chicago, IL. 2007. - this is not even available as an abstract, but is widely cited; a reference to it an be found in the following article:

Travi, Giovanna, and Steven A. Pergam. "Cytomegalovirus pneumonia in hematopoietic stem cell recipients." Journal of intensive care medicine 29.4 (2014): 200-212.

Ljungman, Per, et al. "Definitions of cytomegalovirus infection and disease in transplant patients for use in clinical trials." Clinical Infectious Diseases (2016): ciw668.