Opportunistic infection

An opportunistic infection is an infection by an organism that causes little or no disease in an immunocompetent host but exploits a defect in cell-mediated immunity, neutropenia, humoral deficiency or a breached anatomical barrier, and the category spans bacteria, fungi, protozoa and viruses and is defined by the host rather than by the organism.

It is a leading cause of death in advanced HIV disease and a major complication of chemotherapy, transplantation and biological immunosuppression, accounting for most of the roughly 630,000 AIDS-related deaths recorded worldwide in 2022.

Terminology and classification

• An opportunistic infection is an infection caused by a pathogen that rarely produces disease in a healthy host but exploits a defect in immunity or a breach of an anatomical barrier.
• The term describes a category of infections rather than a single disease, and the responsible organisms span bacteria, fungi, protozoa and viruses.
• Opportunistic pathogens are often commensals that become pathogenic when the microbiome, the skin or the mucosal barrier is disrupted.
• The concept overlaps with healthcare-associated infection and with device-related infection, but not every hospital-acquired infection is opportunistic.
• ICD-10 and ICD-11 do not provide a single code for opportunistic infection, and episodes are coded by pathogen and by the underlying immunodeficiency, such as the HIV disease codes B20 to B24.
• For interoperability the MeSH heading D009894 and the UMLS concept C0029118 are used, and the corresponding Wikidata item is Q835718.
• The distinction between colonization and invasion is central, because many opportunistic organisms can be cultured from healthy people without causing disease.

History

• The concept took shape in the 1950s and 1960s, when corticosteroids, cytotoxic drugs and organ transplantation created populations of patients with iatrogenic immunodeficiency.
• Pneumocystis pneumonia emerged as a characteristic complication of transplant and leukaemia treatment in the 1960s and 1970s.
• On 5 June 1981 the United States Centers for Disease Control reported Pneumocystis pneumonia in five previously healthy gay men, the first published signal of the AIDS epidemic.
• In the 1980s the CDC defined a list of AIDS-defining opportunistic infections that became the basis for surveillance and for treatment guidelines.
• Zidovudine was approved in 1987, and combination antiretroviral therapy from 1996 onwards produced a sharp decline in the incidence of opportunistic infections in wealthy countries.
• Prophylaxis guidelines linked to CD4 counts were introduced in the 1990s and were later consolidated by the CDC, the National Institutes of Health and the HIV Medicine Association.
• Transplant prophylaxis and modern antifungal therapy extended the same preventive logic to non-HIV immunosuppression.

Epidemiology

• About 39 million people were living with HIV in 2022, and roughly 630,000 died of AIDS-related causes, with opportunistic infections responsible for most of those deaths.
• Tuberculosis is the leading cause of death among people with HIV, and it behaves as an opportunistic infection in advanced immunodeficiency.
• Pneumocystis pneumonia remains the most common AIDS-defining infection in many high-income settings and a major cause of admission in low-income settings.
• Among solid organ transplant recipients, infection causes roughly 15 to 20 percent of deaths, with cytomegalovirus and Pneumocystis among the leading pathogens.
• Patients with neutropenia after chemotherapy have a high risk of bacteraemia, and Gram-negative organisms predominate when neutropenia is prolonged.
• Mortality from Pneumocystis pneumonia in hospitalised patients remains around 10 to 30 percent despite effective antimicrobial treatment.
• Surveillance data come from UNAIDS, the World Health Organization, the CDC and transplant registries, and all show that the burden is concentrated where access to antiretroviral therapy and prophylaxis is limited.

• In historical cohorts of patients with CD4 counts below 200 cells per microlitre who did not receive prophylaxis, Pneumocystis pneumonia developed within one year in about 20 to 25 per cent, and trimethoprim-sulfamethoxazole prophylaxis reduced that risk by more than 90 per cent.

Pathophysiology

• CD4 T cell depletion below 200 cells per microlitre removes the cellular immunity that controls Pneumocystis, Toxoplasma, Cryptococcus and Mycobacterium avium.
• Neutropenia below 500 cells per microlitre impairs phagocytosis and is the main driver of bacterial and invasive fungal infection after chemotherapy.
• Defects in humoral immunity predispose to encapsulated bacteria such as Streptococcus pneumoniae and Haemophilus influenzae.
• Breached barriers from catheters, surgery, burns or endoscopy allow skin and environmental organisms to enter normally sterile sites.
• Antibiotic disruption of the gut microbiome permits Clostridioides difficile overgrowth and loss of colonization resistance.
• Biofilm formation on prosthetic material protects organisms such as Staphylococcus epidermidis and Cutibacterium acnes from antibiotics and phagocytes.
• Immune reconstitution inflammatory syndrome occurs when restored immunity reacts vigorously to residual antigen, producing paradoxical worsening after antiretroviral therapy or neutrophil recovery.

Clinical features

• Presentations are often insidious and atypical because inflammation is blunted by immunosuppression, so fever may be absent and imaging changes may be subtle.
• Pneumocystis pneumonia causes progressive dyspnoea, dry cough and hypoxaemia with a chest examination that sounds surprisingly normal.
• Toxoplasmosis typically produces ring-enhancing brain lesions with headache, fever, seizures and focal neurological deficits.
• Cryptococcal meningitis presents with headache, low-grade fever and neck stiffness, and it can progress over weeks.
• Cytomegalovirus retinitis causes floaters and visual loss and is a sight-threatening emergency in advanced AIDS.
• Disseminated Mycobacterium avium complex disease produces fever, night sweats, weight loss and diarrhoea.
• Severe sepsis, respiratory failure and multi-organ dysfunction are the final common pathway, and the risk of death rises with delay in diagnosis.

Diagnosis

• The CD4 count and the type and duration of immunosuppression define the differential, so the first step is to characterise the immune defect.
• Microbiological confirmation is essential, using culture, polymerase chain reaction, antigen testing and microscopy on appropriate specimens.
• Pneumocystis pneumonia is diagnosed by induced sputum or bronchoalveolar lavage with silver staining or polymerase chain reaction, and serum beta-D-glucan supports the diagnosis.
• Cryptococcal antigen testing on serum or cerebrospinal fluid is a rapid and highly sensitive test for cryptococcosis.
• Imaging guides biopsy, with chest computed tomography showing ground-glass opacity in Pneumocystis pneumonia and magnetic resonance imaging showing ring enhancement in toxoplasmosis.
• Differential diagnosis includes non-infectious causes such as drug fever, lymphoma, pulmonary embolism and immune reconstitution inflammatory syndrome, as well as tuberculosis and conventional bacterial pneumonia.
• Screening before immunosuppression, including latent tuberculosis testing, cytomegalovirus serology and hepatitis B and C serology, prevents predictable reactivation.

Management

• Treatment combines pathogen-directed antimicrobial therapy with restoration of immunity, either by antiretroviral therapy or by reducing immunosuppressive drugs when this is safe.
• Pneumocystis pneumonia is treated with trimethoprim-sulfamethoxazole, and adjunctive corticosteroids are added when the arterial oxygen pressure is below 70 millimetres of mercury.
• Toxoplasmosis is treated with pyrimethamine plus sulfadiazine and folinic acid, with trimethoprim-sulfamethoxazole as an alternative regimen.
• Cryptococcal meningitis requires amphotericin B plus flucytosine for induction, followed by fluconazole consolidation and maintenance.
• Cytomegalovirus disease is treated with ganciclovir or valganciclovir, and retinitis may also require intravitreal injections.
• Disseminated Mycobacterium avium complex is treated with a macrolide plus ethambutol, and prophylaxis with azithromycin is used when the CD4 count is below 50 cells per microlitre.
• Prophylaxis thresholds, drug interactions with antiretroviral therapy and management of immune reconstitution inflammatory syndrome are core components of long-term care.

• Drug interactions are managed by avoiding rifampicin with protease inhibitors, and therapeutic drug monitoring of voriconazole and posaconazole is recommended in transplant recipients because absorption and clearance vary widely.

Research and controversies

• When to stop prophylaxis is debated, and current guidance allows discontinuation of primary prophylaxis once the CD4 count has stayed above 200 cells per microlitre for three to six months on antiretroviral therapy.
• Immune reconstitution inflammatory syndrome is poorly predicted, and the role of corticosteroids in its treatment depends on the pathogen and the severity.
• Antimicrobial resistance among opportunistic pathogens, including carbapenem-resistant Pseudomonas and azole-resistant Aspergillus, is a growing threat.
• New antifungals such as ibrexafungerp and fosmanogepix are in development for resistant and refractory invasive fungal infection.
• Vaccine strategies for immunosuppressed patients remain underused, although conjugate pneumococcal and influenza vaccination are recommended.
• The optimal duration of cytomegalovirus prophylaxis after transplant is still debated, and newer assays of cell-mediated immunity may allow shorter courses.
• In resource-limited settings, access to rapid cryptococcal antigen testing, amphotericin B and antiretroviral therapy remains the principal barrier to reducing mortality.