Secondary causes of immunodeficiency
Secondary causes of immunodeficiency are far more common than primary causes. Levels of immune components, as in any system, represent the net balance of component synthesis versus consumption, catabolism or loss. Low levels reflect either depressed production or accelerated consumption (Fig. 1).
Fig1. Common causes of secondary immunodeficiency.
Protein loss severe enough to cause low antibody levels and hypoproteinaemia occurs mainly via the kidney (the nephrotic syndrome) or through the gut (protein- losing enteropathy). The primary diagnosis of nephrotic syndrome usually presents little difficulty; renal loss of immunoglobulin is at least partially selective, so that IgA and IgM levels are maintained despite the fall in serum IgG and albumin. Recurrent infections are rarely a significant problem as specific antibody syn thesis is intact. Protein can also be lost from the gut in a variety of active inflammatory diseases such as Crohn’s disease, ulcerative colitis or coeliac disease. In intestinal lymphangiectasia, the dilated gut lymphatics leak lymphocytes as well as proteins.
Impaired synthesis is exemplified by malnutrition. Severe protein deficiency causes profound changes in many organs, including the immune system. Malnourished people show an increased incidence of infectious disease but the association is complex, since low- grade infection itself may cause malnourishment. Impaired specific antibody production following immunization, and defects in cell- mediated immunity, phagocyte function and complement activity, are associated with extreme poor nutrition. These reverse after adequate protein and caloric supplementation of the diet.
Patients with malignant monoclonal lymphoproliferative diseases are very prone to infection. Untreated chronic lymphocytic leukaemia is often associated with antibody failure and recurrent chest infections, which tend to become more severe as the disease progresses. Non- Hodgkin’s lymphoma may be associated with defects of both humoral and cell- mediated immunity. Hodgkin’s disease is usually associated with marked impairment of cell- mediated immunity. Chemotherapy for lymphoma, usually with an anti- B- cell agent, often results in secondary antibody deficiency as well as reduced B cells; the B- cell component may not recover and secondary panhypogammaglobulinaemia may ensue.
The infection risk in patients with multiple myeloma is five- to tenfold higher than in age- matched controls. Initially, the plasma- cell tumour mass is treated aggressively with chemotherapy. Even before treatment, there is considerable suppression of polyclonal (non- paraprotein) antibody production and chemotherapy results in added suppression of T cells and phagocytic cells. The resultant infections reflect combined B- and T- cell deficiencies and thus may be bacterial, viral or fungal. During remission (plateau phase) the incidence and range of infections decrease; infections at this stage are mainly bacterial, reflecting the dominant polyclonal humoral immune suppression, unless HSTC is done.
The frequency of opportunistic infections in patients with disseminated non- lymphoid malignancies suggests a significant underlying immune defect, although it is difficult to distinguish between the immunosuppressive effects of the disease and those of the treatment. Immunosuppressive drugs affect lymphocyte and neutrophil activity, and low antibody levels are unusual. Patients on drugs to prevent organ transplant rejection also develop unusual opportunistic infections. Another iatrogenic form of secondary immune deficiency is that associated with splenectomy. Every year there are deaths from sudden, overwhelming infection due to Streptococcus pneumoniae in patients who have been splenectomized, often years before. The overall risk of death from infection following splenectomy is 1–2% over 15 years. All such patients should receive immunization with pneumococcal conjugate vaccine as well as prophylactic penicillin and be vaccinated against Haemophilus influenza type b and N. meningitides, as these encapsulated organisms can cause significant morbidity and mortality in asplenic patients.
In a number of infections, the microorganism paradoxically suppresses rather than stimulates the immune system. Severe, though transient, impairment of cell- mediated immunity has been noted in many viral illnesses, particularly cytomegalovirus, measles, rubella, infectious mononucleosis and viral hepatitis. However, the most florid example is infection with HIV.
Acquired immune deficiency syndrome
Acquired immune deficiency syndrome (AIDS) is the final stage in the progression of infectious disease caused by HIV. According to a United Nations report in 2019 (UNAIDS), 1.7 million people became newly infected with HIV in 2018 worldwide. Since 2010, new HIV infections have declined by an estimated 16%, from 2.1 million to 1.7 million. AIDS- related deaths have been reduced by more than 56% since the peak in 2004 (1.7 million deaths in 2004 versus 770 000 deaths in 2018). In 2018, there were 38 million people living with HIV worldwide. Sub- Saharan Africa is the region most affected and accounts for 70% of all people living with HIV, with nearly 1 in every 20 adults living with HIV.
HIV produces a spectrum of disorders from a transient, acute glandular fever- like illness to life- threatening tumours and opportunistic infections. HIV also causes dementia, auto immune disorders and atrophy of particular organs (e.g. brain).
Of the global spread of HIV infection, 70% is thought to be by heterosexual transmission. In contrast to the USA and Europe, the African male- to- female ratio of cases is almost 1: 1, with severe implications for the numbers of infants born to HIV- positive mothers. The prognosis was dismal prior to anti viral therapy, but new therapeutic regimens have changed the outlook for HIV- infected individuals. Politicians and drug companies are now finding ways to bring these expensive therapies to patients everywhere.
Transmission of human immunodeficiency virus infection
HIV has been isolated from semen, cervical secretions, lymphocytes, cell- free plasma, cerebrospinal fluid, tears, saliva, urine and breast milk. Not all these fluids transmit infection, since the concentration of virus varies considerably; semen, blood, breast milk and cervical secretions have been proven to be infectious.
Transmission occurs mainly through sexual intercourse, heterosexual or homosexual. To reduce transmission significantly, educational and awareness policies are essential. Many countries in sub- Saharan Africa have introduced voluntary counselling and testing programmes and there is good evidence that these can change HIV- related sexual risk behaviours, thereby reducing HIV- related risk. Epidemics in men who have sex with men are reemerging in many high- income countries and are gaining greater recognition in many low- income and middle- income countries. HIV prevention strategies using preexposure pharmacological prophylaxis (PrEP) using antiretroviral drugs such as emtricitabine have been shown to be effective for this group. Transmission can also occur via blood and blood products. Sharing of contaminated needles and syringes by intravenous drug abusers, and by therapeutic procedures in areas of the world where reuse of contaminated equipment occurs, can result in HIV (and other viral) transmission. There should be no new HIV seroconversions in blood product recipients in countries in which blood is now screened and blood products treated to inactivate any possible virus. Vertical transmission from mother to child in utero or at delivery is the dominant route of infant infection, although fewer than 20% of children born to HIV- positive mothers become infected. Since maternal antibody to HIV crosses the placenta, a positive test in an infant does not indicate infection. Vertical transfer of HIV may also occur after birth through breast milk. Neonatal diagnosis depends on detection of nucleic acid (by PCR) or viral antigen (by enzyme- linked immunosorbent assay, ELISA) and the mother must be tested also. In a previously undiagnosed family it is essential to test both parents: the mother for vertical transmission and the father in case the mother is recently infected but as yet HIV antibody negative due to the window period.
Seroconversion of healthcare workers is still reported after a needle stick injury, but there is no evidence, despite many studies, that the virus is spread by mosquitoes, bed bugs or swimming pools, or by sharing eating utensils or toilets with an infected person.
The clinical spectrum of human immunodeficiency virus infection
HIV produces a spectrum of disorders (Fig. 3.14). A transient, acute glandular fever- like illness occurs first in patients, but this usually goes unsuspected. Like other viral illnesses, this is accompanied by finding atypical lymphocytes and an increased number of CD8+ T cells in the blood, followed by seroconversion; the time interval between infection and the production of antibodies to HIV (the ‘window period’) may be as long as 6 months.
Most HIV- seropositive individuals then remain symptom free for up to 10 years; development of AIDS depends on the contribution of many co- factors such as genetic background (those with HLA- B57 or HLA- B27 have a better prognosis), repeated stimulation by foreign antigens (multiple co- infections speed the rate of progression) or pregnancy. Almost all patients developed recurring opportunistic infections in the early stages before antiviral therapy. Some individuals develop asymptomatic persistent generalized lymphadenopathy, while others suffered from autoimmune diseases (Fig. 1). The most important prognostic factor for progression to AIDS is the concentration of HIV- RNA in the blood – “viral load” – at diagnosis.
The major clinical manifestations of AIDS are tumours and opportunistic infections. Kaposi’s sarcoma (due to HHV8) is the commonest tumour, but non- Hodgkin’s lymphoma (due to EBV) of B- cell phenotype and often within the central nervous system, and squamous carcinoma of the mouth or anorectum (due to HPV), are also frequent. The many opportunistic infections affect virtually all systems of the body; however, the commonest organs involved are the lung, gut and central nervous system (Fig. 1).
HIV is neurotrophic as well as lymphotrophic: acute aseptic meningitis, encephalopathy, myelopathy and neuropathy have been reported around the time of seroconversion, while chronic meningitis, lymphoma, encephalopathy and dementia may occur later. Around 70% of AIDS patients suffer from HIV- related dementia, which is probably a direct effect of HIV. Despite the arrival of combination antiretroviral therapy (cART), with reduced incidence and improved survival, the spectrum of central nervous system diseases has remained relatively unchanged. However with long life spans, the incidence of clinical symptoms suggestive of IgE- mediated allergic dis ease in individuals infected with HIV has become apparent.
Most patients in the USA and Europe present with Pneumocystis jirovecii. pneumonia, other opportunistic infections or Kaposi’s sarcoma. The presentation in African patients is different: in Africans, AIDS is characterized primarily by a diarrhoea–wasting syndrome (‘slim disease’), Kaposi’s sarcoma and opportunistic infections such as tuberculosis, cryptococcosis or cryptosporidiosis. Infants with HIV infection (<20% of those born to HIV- infected mothers) present at around 6 months, while cases associated with other forms of transmission (e.g. dirty needles for immunization) present later. These children fail to thrive and nearly all have oral candidiasis and recurrent bacterial infections. Chronic interstitial pneumonitis is characteristic. In the late stage, typical opportunistic infections may occur, but Kaposi’s sarcoma and other tumours are rare.
Once AIDS has developed, the prognosis is dismal if untreated. Prior to antiviral therapy, survival was about 9–12 months for patients with P. jirovecii pneumonia, 6–12 months for other opportunistic infections and 20–30 months for Kaposi’s sarcoma. The survival time for patients treated with new therapies will depend on previous treatment (due to viral resistance to the drug), size of the viral load, HLA type of patient and, of course, the virulence and genetic mutation rate of the virus. Rare resistance to HIV in those exposed repeatedly is associated with particular genetic variants of CCR5, a chemokine receptor used for entry of the virus; these resistant patients are known as long- term survivors.
Immunopathogenesis of acquired immune deficiency syndrome
AIDS is a pandemic form of immunodeficiency, caused by several different variants of HIV retroviruses. Retroviruses belong to the lentivirus group, so called for the slow development of the disease. They are RNA viruses that possess a unique enzyme, reverse transcriptase, to synthesize virus- specific double- stranded DNA from the viral RNA genome (Fig. 2). The new DNA is integrated into the genome of the infected cell and may remain latent in these cells. Once reactivated, viral DNA is used as a template for the RNA required for virus pro duction. Viral release takes place at the cell surface by budding; the envelope of the virus is formed from the host cell mem brane, modified by the insertion of viral glycoproteins.
Fig2. Potential therapies for human immunodeficiency virus (HIV) disease. Reverse transcriptase can be inhibited not only by nucleoside analogues, but also by nucleotide analogues and by non- nucleoside substances. Entry inhibitors include fusion inhibitors (such as enfuvirtide) and receptor blockers (maraviroc, an entry inhibitor that binds to the CCR5 receptor and acts as an allosteric blocker). RT, reverse transcriptase.
HIV enters susceptible cells either through binding of viral envelope glycoprotein (gp120) to specific receptors on the cell surface or by fusion between the viral lipid envelope and the target cell membrane. The variant of HIV determines the major route of entry. Lymphotrophic variants use the CD4 molecule itself, with CXCR4 as a co- factor. Cells, such as macrophages and dendritic cells, with low levels of surface CD4 are infected via the chemokine receptor, CCR5. Other cells, such as glial cells of the central nervous system and epithelial cells in the gut and uterine cervix, have different receptors for HIV and are also susceptible. At mucosal surfaces, where contact with HIV usually occurs, infection occurs predominantly either in the mucosal cells themselves or in intraepithelial dendritic cells; these cell types can then pass the virus to CD4 cells by fusion of the viral lipid envelope and the target cell membrane, bypassing any neutralizing antibodies that may be present.
Since HIV replicates at a rate of 109–1010 new virions per day, resulting in as many as 108 new mutants per day, the immune response has an enormous task to limit HIV. In addition, the fast replication results in intrinsically unstable B- cell- binding epitopes and production of high- affinity anti bodies for neutralization does not keep up with the mutations. Cytotoxic T cells are less susceptible since, depending on the HLA type, they bind to more stable epitopes.
HIV- associated disease is characterized by major defects in immunity, following the elimination of CD4 cells. When nor mal CD4 T lymphocytes are stimulated by antigen, they respond by release of lymphokines, including IL- 2, interferons and B- cell growth factors; these regulate growth, maturation and activation of cytotoxic T cells (antiviral), macrophages (antiintracellular bacteria, protozoa and fungi) and NK cells (involved in tumour surveillance). The most striking effects of HIV are therefore on T- lymphocyte- mediated responses. As with other viruses that affect the immune system, autoimmunity and malignancies (both lymphoid and non- lymphoid) reflect loss of immune regulation due to HIV.
Diagnosis of human immunodeficiency virus infection
Primary HIV infection in adults provokes antibodies to the virus envelope and core proteins that are the principal evidence for HIV infection, provided infection with HIV is >6 months prior to testing. These antibodies are directed typically at the envelope glycoproteins (gp120 and gp41) and are detectable throughout most of the life of the infected host. As in other viral infections, anti- HIV antibodies only provide indirect evidence of past infection. Absence of antibody, as in the ‘window period’, does not exclude the presence of the virus, which can be detected by PCR amplification.
The hallmark of disease progression, in addition to development of new symptoms, is an inexorable fall in the absolute number of CD4+ T cells (Fig. 3). As in other virus infections, there may be a rise in the number of CD8+ suppressor/cytotoxic cells within a few weeks of infection but, subsequently, seropositive asymptomatic individuals may have normal numbers of circulating lymphocyte subsets until disease progression begins. Lymph- node biopsies at this stage show many enlarged follicles, often infiltrated by CD8 lymphocytes, with depletion of CD4 cells, and destruction of the normal network structure.
Fig3. Chronology of human immunodeficiency virus (HIV)- induced disease correlated with time since infection. CD4+ T- cell depletion, immunopathology and CDC classification. ARC, acquired immune deficiency syndrome (AIDS)- related complex; CD4, CD4+ T lymphocytes; CNS, central nervous system; NHL, non- Hodgkin’s lymphoma.
Later, polyclonal B- cell activation results in a rise of serum immunoglobulin concentrations in 80–90% of patients with AIDS, including high levels of serum IgE.
Therapeutic options in acquired immune deficiency syndrome
Management of complications involves early recognition of opportunistic infections. Responses to new antigens are impaired as a result of dysfunction of CD4+ dendritic cells. Even in patients with widespread opportunistic infections, there may be no detectable antibody response. Consequently, conventional serological diagnosis of intercurrent infections is unreliable in those with AIDS; PCR is essential. In infants, the failure of antigen presentation and the subsequent humoral immune defect result in repeated bacterial infections. Immunization with pathogen- specific vaccines, including live vaccines such as measles, mumps and rubella (MMR) and BCG, have been shown to be safe in all but the most immunosuppressed children and are usually recommended in order to give as much protection as possible.
Knowledge of the way in which HIV gains access into cells and its method of replication has led to exploration of potential therapies (Fig. 2). Attempts to provide antibodies to block binding of receptors on the viral envelope have so far proved fruitless. To be protective, antiviral antibody must also be neutralizing, although, even so, prevention of cell- to- cell spread by syncytium formation is very difficult. Once long- lived memory T cells are infected, patients are difficult to treat; additionally, macrophages and dendritic cells act as reservoirs of infection as well as a means of spread to the brain.
Inhibition of viral replication is achieved by inhibiting activity of reverse transcriptase (RT), as this is a unique retroviral enzyme with no mammalian counterpart. Zidovudine is an analogue of thymidine that yields inactive proviral DNA and was the first drug approved to treat HIV. Patients who received zidovudine alone had significantly improved survival due to slowing of viral replication, but this allowed viral resistance to develop and, coupled with significant bone marrow toxicity, it is no longer used alone but in combination therapy called highly active antiretroviral therapy (HAART). Zidovudine is included in the Essential Drugs List of the World Health Organization, which is a list of minimum medicinal needs for a basic health care system.
Other agents have been developed (see Fig. 3). Less toxic nucleoside analogues enable lower doses of zidovudine to be used in combination regimens; these have slowed progression significantly in patients with less advanced disease. A major advance was the advent of protease inhibitors, which prevent the assembly of new infectious viruses. The efficacy of this type of treatment was demonstrated even in advanced cases. However, resistance to protease inhibitors, as well to some nucleoside analogues, appears after only a few days. By contrast, resistance to zidovudine takes months to develop, as it requires three or four mutations in the viral RT, whereas a single mutation can confer resistance to the protease inhibitors and other RT inhibitors. The advent of enfuvirtide, a fusion inhibitor that bars the entry of the virus by preventing viral fusion via envelope gp41 with the membrane of the cell, showed improved efficacy. Maraviroc, an entry inhibitor, binds to the CCR5 receptor and acts as an allosteric blocker.
Therapy for HIV infection needs, as do all medicines, to be safe, reliable, avoid the development of resistance and easy to comply with. Once- daily single- tablet regimens represent the ideal. cART aims to meet these requirements and the gold standard of the starting therapy, since approval in 2006, has been efavirenz (a non- nucleoside RT inhibitor) combined with tenofovir disoproxil fumarate or emtricitabine (nucleotide analogue reverse transcriptase inhibitors, NRTIs). Further combination with newer integrase inhibitors and protease inhibitors along with the pharmaco- enhancer cobicistat will promote further ease of compliance and help to optimize regimens that currently may involve up to 20 tablets per day. Combinations of drugs and early treatment are therefore important and reduce the viraemia quickly; monitoring with quantitative measurements of viral load enables tailoring of the dose, resulting in improved compliance and therefore efficacy of drug therapy. Within weeks of starting treatment, the viral load drops below the limit of detection and the CD4 count rises in the blood, due to the mobilization of new CD4 cells from lymphoid tissues and prevention of reinfection of the new T cells, provided compliance with HAART is complete.
Monitoring for therapeutic purposes routinely involves regular viral load measurements and frequent measurements of absolute numbers of CD4+ T cells, with serum β2- microglobulin levels. Prophylaxis against Pneumocystis infection is started when the circulating CD4 count falls below 0.2 × 109/l. Prophylactic antibiotics and antiviral agents have reduced the risk of opportunistic infections, although these now occur later in the disease rather than being prevented totally. The high rate of replication allows the accumulation of numerous variants of HIV over time and many of these are resistant to antiviral therapy. Considerable mortality from HIV remains. In 2011, 1.7 million AIDS- related deaths occurred worldwide.
The response of CD8+ lymphocytes early in infection and the finding that some individuals have mounted a brisk cytotoxic T- cell response, leading to apparent clearance of HIV, have encouraged potential vaccine therapy. Traditional vaccines, using killed or attenuated organisms, are unlikely to be of value, since the fragile nature of the HIV envelope makes it a poor immunogen and the high mutation rate poses difficulties of selecting a stable, common epitope to provoke useful immune responses. Since mutation of an attenuated HIV back to its virulent state would be catastrophic, safety concerns are paramount and these exclude live virus vaccines. Despite these challenges, there has been some scientific progress in recent years. In 2009, a large- scale clinical trial known as RV144 demonstrated that an HIV- 1 vaccine could modestly reduce the incidence of HIV- 1 infection. This trial used a live recombinant viral vector and patients were boosted with protein- based vaccine using HIV gp120, a prime- boost approach, but the reduction was only 31% and the effect was transient. Attempts to make neutralizing monoclonal antibodies (such as VRC01, a human monoclonal antibody capable of neutralizing over 90% of natural HIV- 1 isolates in vitro) have revealed new opportunities for vaccine design once conserved but important epitopes have been identified. In 2012, RV144 vaccination was shown to induce antibodies that targeted a region that contains conserved epitopes. However, success is elusive and currently the most effective controls for HIV diseases continue to be education and prevention.
Infections in the immunosuppressed host
People who are medically immunosuppressed are also predisposed to infection. Such immunocompromised patients are at risk from two sources: they can be infected by common pathogens that invade even the immunologically healthy, or by truly ‘opportunistic’ agents, i.e. those organisms that inflict damage on weakened hosts (Fig. 4). Opportunistic agents account for only one- third of infections, but are responsible for most infective deaths.
Fig4. Organisms causing infections in patients on immunosuppressive treatment.
This highlights two fundamental points about infections in the compromised host: first, most infections are due to common pathogens – these are usually readily identified and controlled by appropriate therapy; second, difficult problems are those caused by opportunistic organisms, because these are often elusive or impossible to isolate and they may not respond to available drugs. In practical terms, therefore, the clinician needs to know when to suspect opportunistic infections.
Several studies have documented diagnostically helpful pat terns of infection in the immunosuppressed host. The best- studied patients are those who have undergone renal transplantation. The major causes of infection in the first month are bacteria related to surgical wounds, indwelling cannulae or postoperative lung infections. After 1–4 months of therapeutic immunosuppression, cytomegalovirus infection dominates a picture that includes various fungal, viral and protozoal infections. Infections occurring beyond 4 months are due either to chronic viral infections, occasional opportunistic infections or infections normally present in the community.
The major portal of entry of opportunistic organisms is the oropharynx, so the lung is the commonest site of infection in the compromised host. The clinical picture is non- specific: fever, dyspnoea and an unproductive cough with widespread pulmonary infiltrates on chest X- ray. Unfortunately, sputum, blood cultures and serology are of little help in identifying the organism; more invasive methods such as bronchoalveolar lavage, transbronchial biopsy or open lung biopsy are frequently needed. The importance of early diagnosis and treatment (where feasible) is emphasized by the grim results: the overall mortality usually exceeds 50%, largely due to rapid progression in immunocompromised patients combined with lack of effective specific therapies for many opportunistic pathogens. However septicaemia, meningitis and gastrointestinal infections with local spread to the liver are not uncommon, though diagnosed more effectively.
