This virus has come up twice in the college exams. Question 4 from the first paper of 2019 involved immunocompromised patients, whereas in  Question 21 from the second paper of 2010 the college had asked specifically about infection in the immunocompetent host. 

Oh's Manual only discusses cytomegalovirus in the context of organ or bone marrow transplants, as well as pediatric pneumonia and encephalitis. One my need to resort to Harrison's (Ch. 182) for more details.

A brief summary of what a CICM trainee is expected to know about CMV has been cobbled together from this chapter, as well as from articles such as this piece by Gandhi et al (2004).

CMV among the immunocompetent ICU population is also explored in this 2008 JAMA paper, andits complications are detailed in this excellent CID article from 1997.

Virology

  • CMV is a β-herpesvirus.
  • It has double-stranded DNA.
  • Replicates in the nucleus.
  • Able to replicate in a variety of cell types.
  • May be present in breast milk, saliva, feces, and urine.
  • Not readily spread by casual contact. Requires prolonged or intimate exposure.
  • Once infected, it is carried for life.
  • Reactivation occurs when T-cell immunity is impaired.
  • In organ transplant recipients, the transplanted organ is often the reservoir.

Clinical manifestations of CMV

Disease causd by CMV is generally divided into "CMV syndrome" and "CMV end-organ disease". The actual distinction is probably more relevant to the stratification of patients in trials (Ljungman et al, 2016) rather than as a guide to therapy. For trial purposes, CMV syndrome is  appicabe only to solid organ transplant recipients, and 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
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

Risk factors for reactivation in the immunocompetent ICU population

  • Trauma
  • Burns
  • Severe critical illness (high APACHE score, over 27)
  • Blood transfusion
  • Mechanical ventilation
  • Severe sepsis
  • Prolonged ICU stay
  • Pregnancy

A brief note on the pathology

  • "Cytomegalovirus" is so called because the affected cells are two to four times the size of unaffected cells.
  • These cells typically have large "owl's eye" inclusions
Indirect Consequences of CMV infection
(from this 2013 article)

Immunocompetent host

  • Bacterial sepsis
  • Fungal sepsis
  • Cardiovascular disease
  • Prolonged ventilation
  • Prolonged ICU stay
  • Increased mortality from all causes

Immunocompromised (transplant) host

  • Chronic allograft nephropathy (renal transplant)
  • Hepatic artery thrombosis (liver transplant)
  • Accelerated Hep C recurrence (liver transplant)
  • Bronchiolitis obliterans (lung transplant)
  • New onset NIDDM
  • Post-transplant lymphoproliferative disease

Diagnosis of CMV infection

  • 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 of CMV

There is little literature to guide your decisionmaking in the critically ill immunocompetent host. Fortunately, 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

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.