Immunocompromised Patients

An immunocompromised patient is one whose immune defences are weakened, whether by an inherited (primary) immunodeficiency or, far more commonly, by an acquired (secondary) cause: immunosuppressive drugs, organ or stem-cell transplantation, cancer and its chemotherapy or radiotherapy, HIV infection, and the extremes of age, pregnancy, and critical illness. This state is central to clinical virology because a weakened immune system removes the controls that normally contain infection: viruses that a healthy person would clear, or never notice, can replicate unchecked and cause severe, prolonged, or unusual disease.

Why immunocompromise alters viral infection

A failing immune response alters viral infection in several recurring ways:

• Reactivation of latent virus. The herpesviruses (herpes simplex, varicella-zoster, cytomegalovirus, Epstein-Barr virus, human herpesvirus 6 and 8), and also the polyomaviruses and adenoviruses, establish lifelong latent or persistent infection and reactivate when immune control fails. It is common for several, sometimes all, of the herpesviruses to reactivate in a stem-cell transplant recipient.
• More severe or prolonged disease. Many infections follow the normal pattern but are worse: disseminated rather than localised, fatal rather than self-limited.
• Generalised spread of normally localised infection. Herpes simplex and varicella-zoster, ordinarily confined to skin or mucosa, can disseminate to viscera.
• Occasionally milder disease. Where injury is immune-mediated rather than directly cytopathic, suppression can reduce damage: a renal transplant recipient with hepatitis B may have less liver inflammation.
• Opportunistic and iatrogenic infection. Agents of low pathogenicity cause disease only in this setting, and transfusion or the donor organ itself can transmit cytomegalovirus, Epstein-Barr virus and others to a patient already gravely ill.

The viruses that most characteristically cause severe disease in the immunocompromised host:

Virus	Manifestation in the immunocompromised host
Herpes simplex virus	Disseminated infection, hepatitis, severe and frequent reactivation
Varicella-zoster virus	Haemorrhagic or disseminated varicella-zoster, hepatitis
Cytomegalovirus (CMV)	Pneumonitis, colitis, retinitis, encephalitis
Epstein-Barr virus (EBV)	Post-transplant lymphoproliferative disorder and lymphomas
Human herpesvirus 8	Kaposi sarcoma, primary effusion lymphoma, Castleman disease
Adenovirus	Disseminated infection, pneumonia, hepatitis
BK polyomavirus	Nephropathy, haemorrhagic cystitis
JC polyomavirus	Progressive multifocal leukoencephalopathy (PML)
Measles virus	Giant-cell pneumonia, sometimes without the rash
Hepatitis B and C	Reactivation; faster progression of fibrosis
Parvovirus B19	Chronic infection with pure red-cell aplasia
Human papillomavirus	More rapid progression, reduced clearance

Which immune defect predisposes to which virus

The pattern of infection depends on which arm of the immune system is weakened.

• T-cell (cell-mediated) defects are the most important in virology, because cellular immunity controls the intracellular and latent viruses. They predispose to severe herpesvirus disease (CMV, disseminated herpes simplex and zoster), measles giant-cell pneumonia, JC virus and PML, and the polyomaviruses. This is the defect of HIV, transplantation, and lymphoma.
• Humoral (antibody) defects predispose to severe or chronic enterovirus infection (including chronic meningoencephalitis) and to persistent norovirus and parvovirus B19.
• Neutropenia and barrier breaches (mucositis from chemotherapy, burns, catheters) matter more for bacterial and fungal infection but also open the way to herpes simplex mucositis and skin spread.

The patient groups

• Solid-organ transplant (SOT) recipients carry sustained drug immunosuppression to prevent rejection; the dominant viral problems are CMV and EBV, plus BK in kidney recipients.
• Haematopoietic stem-cell transplant (HSCT) recipients, largely the haematological-malignancy population, pass through deep immunosuppression with a predictable timeline of herpesvirus and respiratory-virus reactivation, compounded by graft-versus-host disease.
• Advanced HIV brings a progressive, CD4-ordered cascade of viral opportunistic infections.
• Cancer and its therapy (cytotoxic chemotherapy, radiotherapy, and B-cell-depleting agents such as rituximab) cause hepatitis B reactivation and herpesvirus disease.
• The very young and very old, pregnancy, and primary immunodeficiency or autoimmune disease on immunosuppressants are smaller but important groups; the pregnancy and neonatal aspects are covered in the Pregnancy and Neonate topic, and congenital immunodeficiency in the relevant childhood material.

The topic is treated in four linked articles, working from the cross-cutting transplant framework through to the viral infections of advanced HIV.

→ See Viral Infection in Transplant Recipients for the cross-cutting framework: the net state of immunosuppression, the donor and recipient serostatus risk, the post-transplant timeline, and prophylaxis versus pre-emptive therapy, across solid-organ and stem-cell transplantation.

→ See CMV in the Transplant Patient for the single most important viral problem of transplantation: serostatus risk, viral-load monitoring, prevention, CMV disease, and resistance.

→ See EBV in the Transplant Patient for post-transplant lymphoproliferative disorder: pathogenesis, EBV-DNA monitoring, and the management ladder.

→ See Viral Infections in Acquired Immunodeficiency Syndrome for the viral opportunistic infections of advanced HIV, their diagnosis and management.

References and recommended reading

• Burrell CJ, Howard CR, Murphy FA. Fenner and White’s Medical Virology, 5th edition. Academic Press / Elsevier; 2017. The conceptual framework for viral infection in the immunocompromised host.
• Korsman SNJ, van Zyl GU, Nutt L, Andersson MI, Preiser W. Virology: An Illustrated Colour Text. Churchill Livingstone / Elsevier; 2012. The opportunistic-viral-infections overview, including the spectrum of more severe disease in the immunocompromised.