Essential Microbiology for Dentistry. 5th ed.

Chapter 30. Human immunodeficiency virus infection, AIDS and infections in compromised patients

Human immunodeficiency virus infection and acquired immune deficiency syndrome

Statistics on the human immunodeficiency virus (HIV) are startling. By the end of 2015, an estimated 70 million people worldwide had been infected with HIV and one-half of these have died of HIV infection or related complications. Globally, 36.7 million people were living with HIV at the end of 2015. Furthermore, approximately 0.8% of adults aged 15-49 years worldwide are living with HIV, although the burden of the epidemic continues to vary considerably between countries and regions. Sub-Saharan Africa is the most severely affected region, with nearly 1 in every 25 adults living with the infection and accounting for 70% of the people living with HIV worldwide (Fig. 30.1). Worldwide, less than one person in five at risk of HIV has access to basic HIV prevention services.

Although HIV infection is now a global pandemic, acquired immune deficiency syndrome (AIDS) was only described in 1981, in young homosexual men in the USA. The disease appears to have originated in Africa, where cases have been revealed from as long ago as 1959. The virus causes depletion of CD4+ T-helper lymphocytes over many years; as a consequence of which, patients succumb to opportunistic infections, particularly Pneumocystis jirovecii pneumonia and oral candidiasis, and neoplasms, especially Kaposi's sarcoma.

After infection with HIV, there is a prolonged asymptomatic period that may last up to 10 years, but the risk of developing severe immunodeficiency and AIDS increases with time. Thus, the clinical spectrum of HIV infection is broad, ranging from asymptomatic or mild infection to severe clinical illness and profound immunodeficiency. The variety of clinical manifestations seen in AIDS has spawned a number of definitions of the disease. However, the US Centers for Disease Control and Prevention has rationalized and revised these to include all patients with CD4+ cell counts of less than 200 per microlitre.

The battle to conquer HIV infection and AIDS is fought on many fronts, consuming millions of dollars, and thus far all efforts at producing a preventive vaccine have failed. However, the introduction of antiviral regimens such as highly active antiretroviral therapy (HAART) has increased life expectancy in HIV infection and dramatically reduced complications, suppressing viral replication to undetectable levels.

The impact of HIV and AIDS on the practice of clinical dentistry has been enormous; first, because of the regimentation in infection control it has spawned throughout the profession, and second, because of the many oral manifestations and their management, of which the practising dentist has to be aware.

Definitions

 HIV infection: infection with the HIV, an RNA retrovirus.

 HIV disease: the resulting immunodeficiency and the appearance of attendant diseases (i.e., not all HIV-infected persons will have symptomatic disease).

 AIDS: a term given to a group of disorders characterized by a profound cell-mediated immunodeficiency consequential to irreversible suppression of T lymphocytes by the HIV. These disorders are called AIDS-defining illnesses and include parameters such as CD4 lymphocyte count below 200 x 106/l, oropharyngeal candidiasis, hairy leukoplakia, etc. (Table 30.1).

Retroviridae

HIV is a lymphotropic virus that belongs to the family Retro- viridae. Retroviridae are RNA viruses; the family comprises three subfamilies:

 Lentiviruses cause slowly progressive disease and are cytopathic in nature; they include HIV-1 and HIV-2.

 Oncoviruses include those that cause tumours: human T cell leukaemia virus type I (HTLV-I), which causes adult T cell leukaemia-lymphoma (ATLL); and HTLV-II, associated with hairy cell leukaemia.

 Spumaviruses are not recognized human pathogens.

Fig. 30.1 A map of global prevalence of HIV infection amongst 15-49-year-olds as of 2015 (Courtesy the World Health Organization).

Table 30.1 Centers for disease control and prevention classification of HIV infection

 

Clinical group

 

Absolute CD4 cell count (x106/l)

A

B

C

>500

A1

B1

C1

200-499

A2

B2

C2

<200

A3

B3

C3

Group A: acute HIV infection, asymptomatic phase or persistent generalized lymphadenopathy.

Group B: symptomatic but not AIDS-defining (see text).

Group C: conditions meeting the Centers for Disease Control and Prevention/ World Health Organization AIDS-defining criteria.

Human immunodeficiency virus

The virus has a diameter of 100 nm, and its structure is described later. There are two types: HIV-1 is the most prevalent; HIV-2 is a variant that originated in West Africa and has spread to Central Africa, Europe and South America. Type 1 is classified into two major groups: M, containing 10 genetically distinct subtypes (A-J), and O, containing a heterogeneous collection of viruses. Type 2 HIV, except for its antigenic and nucleic acid profile, has similar biological properties to HIV-1.

The structure of HIV is shown in Fig. 30.2. It consists of:

1. an envelope containing virus-specific 'coat' proteins (e.g., glycoproteins gp41 and gp120), which can act as antigens. Glycoprotein gp120 has a 'rugger-ball' configuration and plays an important role in the initial events leading to infection. These coat proteins undergo almost continual structural changes, which hamper the development of effective vaccines

2. three core proteins, of which p24 is especially antigenic: antibodies to this form the basis of most serological testing (the HIV test)

3. a genome of RNA comprising two identical molecules of single-stranded RNA

4. two molecules of an enzyme, reverse transcriptase (an RNA-dependent DNA polymerase), essential for transcribing the RNA code of the virus to a DNA code during viral multiplication (so that it may integrate into the host cell DNA).

Stability of HIV

The survival of HIV under varying conditions has been investigated.

 HIV is destroyed by heat (autoclave and hot-air oven); the virus is inactivated by a factor of 100-fold each hour at a temperature over 60°C.

 The virus may survive up to 15 days at room temperature and at body temperature (37°C).

 HIV is totally inactivated (>105 units of infectivity) by exposure for 10 min at room temperature to the following disinfectants: 2% glutaraldehyde, sodium hypochlorite (10 000 ppm available chlorine, equivalent to 1 : 10 dilution of domestic bleach), 50% ethanol, 35% isopropanol or 0.3% hydrogen peroxide.

 When HIV is present in clotted blood in a syringe or other material, exposure to undiluted bleach for at least 30 s is necessary for its inactivation.

Fig. 30.2 Human immunodeficiency virus. (A) Structure; (B) scanning electron micrograph of virions showing the pyramid-shaped central core.

Important: the above figures indicate the limits of survival at very high starting concentrations of HIV (up to 1000 times more than the levels found in the blood of patients) under experimental conditions. Also, the efficacy of the mentioned disinfectants is affected by a variety of factors such as the associated organic bioburden. Hence, care and strict adherence to protocols are essential when dealing with HIV.

Viral replication

See Chapter 10.

Transmission of HIV

The virus is most commonly acquired through sexual activity with an infected partner. The virus can enter the body through the lining of the vagina, vulva, penis, rectum or mouth during sex. The infection can also be transmitted by exchange of infected blood, or other body fluids such as breast milk, and is not transmitted by social or casual, non-sexual contact. Currently, heterosexual sex is the major mode of transmission worldwide. Other notable transmission modes include sharing of needles, vertical transmission in utero, breast-feeding and transfusion of infected blood or blood products (factor VIII concentrate). Occasional cases of HIV infection result from needlestick injuries in health care settings. The question of HIV transmission among health care workers, including dentists, is addressed at the end of this chapter.

Saliva and HIV transmission

There is only a very slim possibility that HIV may be transmitted by saliva, for the following reasons.

1. Only a small minority of HIV-infected individuals harbour the virus in whole saliva (e.g., in one study, HIV was detected in mixed saliva of 5% of infected individuals and in only 1 of 15 parotid saliva samples). In any case, HIV virions cannot exist in a cell-free state in saliva, and estimates indicate that there is less than one infectious particle of HIV per millilitre of mixed saliva.

2. Saliva contains immunoglobulin A (IgA) group antibodies to HIV proteins (p24, gp120, gp160), which may neutralize the infectivity of the virus and are the basis of salivary kits used for HIV-testing in epidemiological studies.

3. Other HIV-inhibitory factors in saliva include high-molecular-weight mucins thought to entrap the virus, proline-rich proteins and a serine protease inhibitor termed salivary leukocyte protease inhibitor (SLPI). SLPI possibly blocks cell surface receptors needed for entry of HIV into cells.

4. The virus loses its infectivity when exposed to mixed saliva for 30 min.

5. Animal studies have shown that it is not possible to transmit HIV by surface application of the virus on the oral mucosa, although it was transmitted in this manner through vaginal mucosa.

6. The dose of HIV required for infection is far higher than that for hepatitis B virus (the risk of acquiring hepatitis B infection from a contaminated needlestick injury is 6%-30%, compared with a 0.4% risk of contracting HIV infection).

Epidemiology

The main groups of individuals affected are:

 promiscuous individuals, both homosexuals and heterosexuals: 75% of all infection has been acquired through sexual intercourse; the current male-to-female ratio is 3 : 2 (infections in homosexuals were levelling off due to increased awareness of the disease and safe-sex practices, but a recent increase has been reported)

 injecting drug abusers: some 10% of infection globally; 26% in the USA

 persons receiving blood or blood products: about 1% globally (mainly a problem of the developed world)

 offspring of infected mothers: varying transmission rates reported, 10%-50%; most infection acquired at birth, with a few acquired in utero and or through breast-feeding accounting for the rest.

The global pandemic

As mentioned earlier, by the end of 2015 an estimated 36.7 million people worldwide were living with HIV, and some 35 million have died of HIV infection or related illnesses since the beginning of the epidemic. Of those succumbing to AIDS, 90% are living in developing countries, especially in Asia and Africa. The estimated annual increase worldwide is about 20%, but this varies widely in different geographic locales. For instance, the annual increase is about 11% in the Americas, 26% in Africa and 167% in Asia, indicating the staggering explosion of the disease in the latter region. In those countries, AIDS is overwhelmingly a heterosexually transmitted disease, and there are about equal numbers of male and female cases.

It is postulated that the rapid dissemination of HIV globally especially in the latter part of the 20th century was promoted by mass migration of rural inhabitants to urban centres together with international movement of infected refugees as a consequence of civil disturbances, tourism, and business travels.

Currently, HIV infection is the leading cause of death in US men aged 25-44 years. In some countries, such as the Ivory Coast, HIV/AIDS is the leading cause of death; and in Uganda, it causes 80% of deaths in adults aged 20-39 years.

Globally, a silver lining in the deadly HIV story is the introduction of anti-retroviral therapy that has reduced HIV infection amongst newborns by 50% since 2010 due to maternal prophylaxis measures, and a 45% drop in AIDS-related illnesses amongst people living with HIV since the peak of 2005.

Acquired immune deficiency syndrome

Natural history of the disease

AIDS is an insidious disease, characterized by opportunistic infections (fungal, viral and mycobacterial), malignancies (especially Kaposi's sarcoma and lymphomas that may be virally induced) and autoimmune disorders (Fig. 30.3).

Fig. 30.3 Key events in HIV infection. PGL, persistent generalized lymphadenopathy.

The average time to development of AIDS is 8-11 years in most adults in the developed world, and much less in the developing world due to aggravating cofactors such as malnutrition and intercurrent infection (e.g., malaria). A few individuals (some 2%) have not developed AIDS despite antibody positivity. Overall, almost half of those diagnosed with AIDS will die. Untreated, the median survival is about 1 year from the time of diagnosis, and 95% will die within 5 years.

Mean time for seroconversion after exposure to HIV is 3-4 weeks, with the onset of an acute seroconversion illness similar to glandular fever. Most will have antibodies within 6-12 weeks after infection and virtually all will be positive within 6 months. Symptoms of such seroconversion include fever, malaise, rash, oral ulceration and, occasionally, encephalitis and meningitis. In some, the disease may then become quiescent and asymptomatic for several years (range 1-15 years or more) for reasons yet unknown. Some of them may have persistent generalized lymphadenopathy (PGL), where the enlarged lymph nodes are painless and asymmetrical in distribution and involve submandibular and neck nodes. In the HIV disease classification, patients with these symptoms are categorized as group A (see Table 30.1).

Progressive disease leads to other features, including fatigue, fever, weight loss, candidiasis, diarrhoea, hairy leukoplakia, herpes zoster and perianal herpes, and these illnesses are sometimes referred to as the AIDS-defining complex. Patients with these symptoms and signs of progressive illness are categorized as group B.

Finally, a percentage of HIV-infected individuals develop full-blown AIDS (50%-70% depending on drug therapy and other associated cofactors; median life expectancy is 18 months). These individuals are in group C. The AIDS-defining conditions are subdivided into opportunistic infections and secondary neoplasms, and include Kaposi's sarcoma, pneumocystis pneumonia (PCP) and many other exotic infections (Table 30.2).

The Centers for Disease Control and Prevention disease classification also incorporates blood CD4 lymphocyte count, as a decrease in the latter is associated with adverse prognosis (see Table 30.1).

Opportunistic infections and neoplasms in AIDS

The opportunistic infections, neoplasms and other features of AIDS and its prodrome are listed in Table 30.2.

Pneumocystis jirovecii pneumonia

This pneumonia is caused by a fungus P. jirovecii, previously thought to be a protozoan (Pneumocystis carinii). The fungus grows within the lung alveoli. Seen in 80% of patients, it is the immediate cause of death in 20% of those dying with AIDS. The condition is treated with aerosolized pentamidine.

Toxoplasmosis

Protozoal infection with Toxoplasma gondii is seen in 15% of AIDS patients, affecting especially the central nervous system.

Atypical mycobacteriosis

Atypical mycobacteriosis is present in about 40% of patients in the West; caused by Mycobacterium avium complex (MAC) infections due to mycobacteria such as Mycobacterium avium and Mycobacterium intracellulare. In some countries, up to a quarter of HIV-positive people are infected with Mycobacterium tuberculosis, which may be increasingly drug-resistant (multidrug-resistant tuberculosis [MDR-TB]: see Chapter 19).

Table 30.2 Opportunistic infections, neoplasms and miscellaneous complications of HIV disease 

Opportunistic infections

Mucocutaneous

Human herpesviruses 1,2, 3, 4, 5, 8

Human papillomaviruses

Molluscum contagiosum

Non-tuberculous mycobacteria

Candida albicans

Staphylococcus aureus

Histoplasmosis

Gastrointestinal

Cryptosporidiosis

Microsporidiosis

Isosporiasis

Giardiasis

Respiratory

Pneumocystis jirovecii

Aspergillosis

Candidosis

Cryptococcosis

Histoplasmosis

Zygomycosis (mucormycosis)

Strongyloidiasis

Mycobacteria, including tuberculosis

Staphylococcus aureus

Streptococcus pneumoniae

Haemophilus influenzae

Toxoplasmosis

Cytomegalovirus (CMV)

Meningitis

Creutzfeldt-Jakob agent

Encephalitis

Papovaviruses

Cryptococcus neoformans

Toxoplasma gondii

Neoplasms

Kaposi’s sarcoma Lymphoma

Squamous cell carcinoma Leukaemia

Miscellaneous

Encephalopathy

Thrombocytopenic purpura

Lupus erythematosus

Seborrhoeic dermatitis

Candidiasis and herpesvirus infections

See later.

Orofacial manifestations of HIV infection

The earliest indicators of HIV infection may manifest in the oral cavity, and some 50 disease entities that may affect the orofacial region of HIV-infected patients have been described. However, with advent of HAART therapy (see later), the prevalence of oral manifestations has dramatically reduced. The more common orofacial manifestations of HIV infection are (Table 30.3):

 fungal infections: oral candidiasis (erythematous and pseudomembranous variants mainly); linear gingival erythema and angular cheilitis (both are possibly due to mixed bacterial and fungal infections)

 viral infections: hairy leukoplakia, Kaposi's sarcoma, herpes infections, papillomas

 bacterial infections: gingivitis and periodontitis

 cervical lymphadenopathy and lymphomas such as non-Hodgkin's lymphomas (not discussed further).

Oral candidiasis

Oral candidiasis (usually erythematous or pseudomembranous candidiasis) is very common in HIV infection, especially at the early stage of the disease; it is a reliable and ominous prognostic indicator of the disease progression to AIDS (the earlier the appearance of oral candidiasis, the worse the prognosis). Oesophageal candidiasis frequently accompanies oral candidiasis and is usually managed by azole drugs, commonly fluconazole. However, azole resistance is increasingly common.

Linear gingival erythema and angular cheilitis are possibly due to mixed fungal and bacterial infections (see Chapter 35).

Viral infections

Viral infections include herpetic stomatitis, herpes zoster, Kaposi's sarcoma and others such as hairy leukoplakia and papillomas of viral origin.

Herpetic stomatitis

A 10% prevalence of herpetic stomatitis in HIV-infected persons has been reported. Herpes simplex infections are mainly intraoral, sometimes extensive and persistent, but rarely disseminate. A minority suffer from herpes zoster and papillomavirus infections. The latter manifests as oral papillomas, warts or condylomata.

Kaposi’s sarcoma

Caused by human herpesvirus 8, this is a multifocal systemic tumour due to proliferating microvascular and fibroblastic processes, seen mostly in sexually transmitted HIV infection.

Hairy leukoplakia

This classically appears as an asymptomatic, greyish-white to white, corrugated lesion on the tongue, either unilaterally or bilaterally (Fig. 30.4). The aetiological agent is the Epstein-Barr virus. (Note: it is also seen in patients belonging to other risk groups, and uncommonly in healthy individuals.) As more than three-quarters of HIV-infected patients with hairy leukoplakia develop AIDS within 3 years, it is considered to indicate a poor prognosis.

Necrotizing (ulcerative) gingivitis and necrotizing (ulcerative) periodontitis

An unusual type of recalcitrant, aggressive periodontal disease has been identified in those who are infected with HIV. The disease begins as a form of gingivitis that mimics acute ulcerative gingivitis. However, it differs from the latter as the disease progresses unceasingly despite routine management protocols such as metronidazole therapy, debridement and scrupulous oral hygiene. The anterior gingiva is most commonly affected. In some patients, HIV gingivitis has a very destructive course, leading to periodontitis with loss of soft tissue and bone, sequestrum formation and, in extreme cases, tooth exfoliation.

Table 30.3 Oral manifestations of HIV disease

Strongly associated

Less common associates

Sometimes seen

Candidiasis

Herpes simplex or zoster infection

Exotic fungal infections (ulcers)

Erythematous

Human papillomavirus infections

Cryptococcosis

Pseudomembranous

Mycobacterial infections

Histoplasmosis

Linear gingival erythema

 

Penicilliosis

Hairy leukoplakia

Kaposi’s sarcoma (not in Asia)

Unilateral/bilateral swelling of salivary glands

Drug reactions

Necrotizing (ulcerative) gingivitis

Dry mouth

Cranial neuropathies

Necrotizing (ulcerative) periodontitis

Ulceration (non-specific) Melanotic hyperpigmentation

Facial palsies

Trigeminal neuralgia

Non-Hodgkin’s lymphoma

 

Recurrent aphthous stomatitis

Fig. 30.4 Hairy leukoplakia of the lateral border of the tongue in a patient with AIDS.

Diagnosis

History and clinical criteria are of utmost importance in the provisional diagnosis of HIV infection but laboratory investigations, after appropriate professional counselling, are required for confirmation of the disease.

The first step in serodiagnosis is the enzyme-linked immunosorbent assay (ELISA) or agglutination screening tests for serum antibodies. Up to about 2% of the ELISA tests are either false positive or false negative: hence a positive ELISA must be retested in duplicate samples. If two or more of the latter three ELISA results are positive, confirmatory testing has to be done by a Western blot assay. Thus the principles and ethics of diagnosis are:

1. Apply a minimum of two methodologically different assays.

2. Repeat the test 2-3 months later, as there is a 'window' period between acquisition of infection and the development of antibodies (see Fig. 30.2).

3. Do not divulge positive results until confirmed using the strictest criteria. Maintain confidentiality of the results at all times.

Other laboratory diagnostic methods include:

 virus isolation mainly from lymphocytes in peripheral blood: essentially limited to research laboratories due to the lengthy and laborious nature.

 detection of viral nucleic acids or antigens by various polymerase chain reaction techniques (very useful for detecting HIV in newborns as their plasma is contaminated with HIV antibodies from the mother).

A high viral load in the plasma of infected individuals predicts a more rapid progression to AIDS than a low viral load.

Management

A number of antimicrobial agents are used in the management of HIV and its related infections. The two main groups of drugs used to suppress HIV proliferation are:

1. Reverse transcriptase inhibitors: these drugs inhibit the reverse transcriptase enzyme of HIV, and are subdivided into:

 nucleoside (analogue) reverse transcriptase inhibitors, including zidovudine (azidothymidine, AZT), the first drug introduced in this category; didanosine (ddI); lamivudine (3TC); stavudine (d4T); and zalcitabine (ddC)

 non-nucleoside reverse transcriptase inhibitors, e.g., nevirapine.

2. Protease (proteinase) inhibitors: saquinavir, ritonavir, indinavir and nelfinavir inhibit proteins essential for viral reproduction, such as reverse transcriptase and integrase.

Other relatively new drugs include fusion inhibitors (approved in 2003), which block HIV envelope from merging with the host CD4 cell membrane; entry inhibitors (2007), which block virus entry into cells; and integrase inhibitors (2007), which interfere with the viral enzyme required for HIV replication

Combination therapy with nucleoside analogues and protease inhibitors is far more effective than monotherapy with individual drugs. However, the side effects and the cost of treatment are both barriers to such 'cocktail' therapy. HAART consists of two nucleoside inhibitors and one protease inhibitor. There is significant clinical improvement in HAART therapy, yet the virus persists intracellularly as a provirus, only to re-emerge if or when therapy is reduced.

A large number of antimicrobial drugs are also used pro- phylactically to prevent emergence of fungal, bacterial and viral infections, and as therapeutic supportive measures to prolong the quality of life in these patients.

Prevention of HIV infection

 Public education programmes aiming at changing sexual behaviour and promoting 'safe sex', especially the use of barrier contraceptives, will continue to be the mainstay of HIV prevention into the foreseeable future.

 Free distribution of sterile needles to injecting drug abusers has proved useful.

 Antiretroviral drugs to HIV-infected mothers and their newborns have been extremely effective with some 50% reduction in infection transmission to the neonates.

 Transmission in health care settings can be prevented by appropriate protective workwear (see Chapter 37).

 The likelihood of an HIV vaccine becoming available within the next 5 years is low, as the virus (1) mutates rapidly from one generation to another, thus evading host immune cells; (2) is not expressed in all cells that are infected; and (3) is not cleared by the host immune cells after primary infection. However, a number of candidate vaccines are undergoing trials, and the approach to vaccine development is shown in Fig. 30.5. A major obstacle for vaccine development is the lack of an appropriate animal model. Chimpanzees are the only HIV-susceptible animals with a viraemia and antibody response, yet they do not develop immune deficiency.

HIV transmission and dental health care workers

The risk to dental professionals

A number of prospective surveillance studies indicate that there is no risk of HIV transmission by either saliva or blood in routine dental care. However, accidental injuries via contaminated needles are associated with a very low risk of infection (0.3%). In view of the thousands of infected patients treated since the advent of the AIDS pandemic, it is highly unlikely that the occupational hazard of dentists contracting HIV infection is greater than that for other health care workers. Additionally, the susceptibility of HIV to many disinfectants, the hygienic environment in most dental surgeries and the use of disposable instruments reduce the risk still further. After close scrutiny of the small number of alleged HIV transmission episodes in dentistry, the US Centers for Disease Control and Prevention have stated that there has been no such transmission in dental settings thus far.

The HIV-infected dental health care worker

The disclosure of possible HIV transmission to five patients by an infected dentist (in Florida, USA) has raised important ethical, moral and legal issues pertaining to continued delivery of dental care by infected dental personnel. (However, the dental transmission route has now been ruled out as it is believed that the patients acquired the infection from high-risk activities.)

Fig. 30.5 Current approaches to HIV vaccine production and post-infection drug therapy.

The consensus of professional opinion is that it is the ethical and moral responsibility of dentists who believe that they may be infected with HIV to obtain medical advice and, if found to be infected, to act upon the medical advice, if necessary by modifying the practice of dentistry in some way or by ceasing practice altogether.

Infections in compromised patients

A compromised patient is a person whose normal defence mechanisms are impaired, making the individual more susceptible to infection (e.g., individuals with damaged heart valves, diabetes and immunodeficiency states, including AIDS).

Although the majority of compromised patients are hospitalized, a significant proportion are ambulant community dwellers and likely to seek routine dental care. It is important to note that the drugs and dental treatment provided may interfere with the compromised state and the medications prescribed.

Mechanisms leading to immunocompromised states

Immunodeficiency disease can be either primary (developmental or genetically determined), which is rare, or secondary, due to procedures such as irradiation and cytotoxic drug therapy.

Primary immunodeficiency

Rarely children are born with congenital deficiency of the immune system. These include deficiencies in B cells, with depressed immunoglobulin production, T cell deficiency (e.g., thymic aplasia), combined B-cell and T-cell deficiency, and neutrophil dysfunction.

Secondary immunodeficiency

Secondary immunodeficiency can be due to disease or therapy (Table 30.4).

Table 30.4 Main causes of secondary immunodeficiency

Drugs

Methotrexate

Cytarabine

Malignant disease

Acute leukaemia

Hodgkin’s disease

Infections

AIDS

Severe viral infections

Deficiency states

Iron deficiency

Autoimmune disease

Rheumatoid arthritis

Others

Diabetes mellitus

Irradiation

_____

Disease

Diseases include neoplasms of the lymphoid system leading to lymphomas (Hodgkin's disease), leukaemia and multiple myeloma, and—of special interest—AIDS due to HIV infection (see earlier). Other diseases such as diabetes, renal failure, rheumatoid arthritis and autoimmune disease (e.g., systemic lupus erythematosus) diminish immunity by often complex and incompletely understood mechanisms.

Therapy

Modern medical treatment, especially drugs, radiotherapy and surgical removal of the spleen, may diminish or abolish immune function:

 drugs: immunosuppressives, cytotoxic drugs and steroid therapy

 radiotherapy is widely used in cancer treatment and is a popular regimen for therapy of head and neck cancer; in addition to the general depressive effect of radiotherapy on immune cells, it has localized effects on salivary glands and oral mucosa, leading to xerostomia and mucositis of the oral mucosa, respectively; the latter results in secondary oral infections

 splenectomy results in increased susceptibility to infection with encapsulated bacteria such as Streptococcus pneumoniae.

Oral infections in compromised patients

Due to the poor immune functionality associated with the specific underlying condition or the management procedure, the oral cavity is perhaps the first site where focal infection may be noted in compromised individuals. Such infections may be caused by endogenous commensal flora of low pathogenicity (e.g., oral candidiasis) or exogenous organisms acquired from the environment (e.g., drug-resistant hospital staphylococci, methicillin-resistant Staphylococcus aureus, coliforms). Both virulent organisms and even the most harmless commensals may cause life-threatening disease (Table 30.5).

Some examples of specific orofacial infections in compromised patients are as follows:

 Osteoradionecrosis. Oral cancer is often treated by radiotherapy, and this may lead to tissue necrosis, including bone, due to decreased number of cells (hypocellularity) and, a reduction in the number of blood vessels (hypovascularity). Resultant death of bony tissue due to a combination of the foregoing effects, or precipitated by trauma (e.g., tooth extraction) may lead to spontaneous bony necrosis, termed osteoradionecrosis. Such necrotic tissue may be secondarily infected by Staphylococcus aureus and/or anaerobes such as Porphyromonas and Prevotella species. Management of the condition, which is rather difficult, is by bone-penetrating antibiotics such as clindamycin and/or metronidazole in combination with surgical debridement, or chlorhexidine irrigation if the site is accessible.

 Bisphosphonate-associated osteonecrosis. Osteoporosis is a common condition that leads to calcium loss from the bone. Bisphosphonates are used to prevent osteoclastic activity and bone loss. A common adverse side effect of bisphosphonates is failure of bone healing, especially after tooth extraction. Such sockets may be secondarily infected by anaerobes, and irrigation of tooth socket with chlorhexidine and metronidazole may be helpful.

Table 30.5 Examples of organisms that cause infection in compromised patients

Agent

Infection

Bacteria

Enterobacteriaceae

Urinary tract infection, pneumonia, septicaemia, meningitis, oral mucositis, osteoradionecrosis

Mycobacterium tuberculosis and other mycobacteria

Tuberculosis, disseminated disease, IRIS

Staphylococcus aureus

Septicaemia, pneumonia, mucositis, osteoradionecrosis

Streptococcus pneumoniae

Septicaemia

Fungi

Candida spp.

Thrush, systemic candidiasis, chronic mucocutaneous disease

Cryptococcus neoformans

Meningoencephalitis

Aspergillus and Mucor spp.

Disseminated disease

Pneumocystis jirovecii

Interstitial pneumonia (in AIDS)

Viruses

Herpes simplex virus

Severe cold sores

Cytomegalovirus

Pneumonia, IRIS

Protozoa

Toxoplasma gondii

Severe toxoplasmosis

IRIS, immune reconstitution inflammatory syndrome.

 Post-irradiation mucositis. Another complication of irradiation is its effect on the oral mucosa, which reacts in the form of non-specific inflammation, termed mucositis. Microflora associated with mucositis are rather non-specific and may include gram-negative aerobes and facultative anaerobes such as Escherichia coli, Klebsiella species and pseudomonads. The condition spontaneously remits after radiotherapy but may be ameliorated by topical application of non-absorbable antimicrobials.

 Necrotizing fasciitis. This is a rapidly progressive, serious infection that may even lead to death and is not uncommon in immunocompromised individuals. Necrotizing fasciitis may be precipitated by dentoalveolar infection, and the implicated aetiological agents include the anginosus group of streptococci and anaerobes such as Prevotella species. Management is by intravenous antibiotics, surgical debridement and hyperbaric oxygen in severe cases.

 Immune reconstitution inflammatory syndrome

(synonym: IRIS, immune recovery syndrome). This newly described condition is seen in some cases of AIDS or immunosuppression, in which the immune system begins to recover, for instance after antiretroviral therapy, but then responds to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse. IRIS is thought to be precipitated by reconstitution of antigen-specific T cell-mediated immunity and activation of the immune system against persisting antigen. The latter may present as intact organisms, dead organisms or debris. Infections most commonly associated with IRIS include cytomegalovirus, herpes zoster, mycobacterium avium complex (MAC), pneumocystis pneumonia and M. tuberculosis. Management is by antibiotic or antiviral drugs against the infectious organism, sometimes with corticosteroids to suppress inflammation.

 Cancrum oris or noma. See Chapter 33.

Important cofactors for oral infection in immunocompromised patients Cofactors important in oral infection include:

 the duration and depth of immunosuppression

 previous or current antimicrobial treatment (e.g., broad-spectrum antibiotics promote fungal infection)

 the degree of oral hygiene and quality of oral care provided

 the nature of the cytotoxic or immunosuppressive drug used (e.g., methotrexate, in particular, causes oral ulceration, which may become secondarily infected).

Clinical presentation

The presentation of oral infections varies widely, depending on the cofactors mentioned earlier. Some conditions are more commonly associated with a particular category of compromised patient than others. For instance, in acute leukaemia, the response to dental plaque is exaggerated, leading to gross gingival swelling, but periodontal disease is not a significant problem during cytotoxic therapy. Oral problems encountered in immunocompromised patients are listed in Table 30.6.

Prevention of infection

General guidelines

Surveillance

Careful monitoring of the susceptible individual for signs of infection is required; if these occur, treatment should be instituted without delay.

Antibiotics

Avoid the abuse of antibiotics (particularly broad-spectrum antimicrobials) to minimize emergence of resistant flora.

Isolation

Severely ill patients (e.g., those with neutropenia) should be either isolated in a single room with only nursing staff admitted, or completely isolated (in a laminar airflow bed or room) and provided with sterilized food.

Specific guidelines

Pretreatment management

Pretreatment management includes:

Table 30.6 Diseases of infective origin seen in different compromised patient populations

Condition

Cytotoxic therapy

Radiotherapy

AIDS

Acute leukaemia

Mucositis

+

+

-

+

Ulceration

+

+

+

+

Xerostomia

+

+

+

-

Sialadenitis

-

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Osteomyelitis

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Candidiasis

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Herpes infection

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Periodontal diseases

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Dental caries

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 a careful assessment of the patient's dental health before radiotherapy or immunosuppressive drugs are used

 appropriate restorative or surgical treatment (e.g., extraction of non-restorable teeth before radiotherapy to prevent osteomyelitis of the mandible)

 oral hygiene instruction and dietary advice (e.g., low-sugar diet, regular fluoride applications).

Management during treatment

 Diagnosis and management should be carried out with the assistance of laboratory tests and reports.

 Oral management of the patients must be closely linked with the medical treatment, and it is essential that the dentist is regarded as part of the medical team.

Xerostomia and infection

Xerostomia or dry mouth may be the result of:

 ageing

 drugs (e.g., cytotoxic therapy)

 radiotherapy

 Sjogren's syndrome (primary and secondary).

The resulting chronic dryness of the mucosa and the inadequate salivary cleansing mechanism increase the susceptibility of oral tissues to incidence of:

 caries

 periodontal diseases

 oral candidiasis

 ascending (bacterial) sialadenitis.

Other non-infective sequelae are difficulty in eating and swallowing dry food, and in wearing complete dentures; burning sensation of the oral mucosa; and changes in the sense of taste (dysgeusia).

A reduction or absence of salivary secretion has a profound effect on the composition of the normal oral flora. Reduced moisture levels tend to favour growth of bacteria resistant to drying, such as Staphylococcus aureus, and inhibit oral commensals adapted to high moisture levels. In addition, the pH of salivary secretions in these patients is low and the oxygen tension (Eh) is high, which may be unfavourable to the growth of bacteria such as Veillonella, commensal Neisseria and Micrococcus spp. Moreover, this environment favours the growth of Candida spp.

Sequelae of chronic xerostomia

Extensive dental caries

Dental caries may occur, especially in the cervical and incisal surfaces of the teeth and at the margins of dental restorations, sometimes subgingivally.

Prevention

Daily fluoride mouth-rinsing; discontinuation of high-sucrose snacks between meals; careful removal of dental plaque by proper, frequent brushing; and regular dental supervision. Severe caries may be controlled by fluoride application.

Periodontal disease

Periodontal disease, especially gingivitis, is common because of the lack of moisture.

Prevention

Mouthwashes containing 2% chlorhexidine will help control gingivitis and other oral infections.

Candidal infections

Candida-associated denture stomatitis, angular cheilitis and papillary atrophy of the tongue are frequent.

Prevention

See Chapter 35.

Ascending parotitis

Ascending parotitis is the result of the absence or reduced natural flushing action of the salivary flow in Stensen's duct.

Prevention

Treat with antibiotics: empirical therapy with penicillinase- resistant penicillins. Pus should be sent for culture and antibiotic sensitivities. Stimulate salivary secretion with sialagogues; if adequate amounts of saliva cannot be stimulated, use a proprietary saliva substitute.

Key facts

 The human immunodeficiency virus (HIV), an enveloped, RNA retrovirus containing the enzyme reverse transcriptase, is the agent of HIV disease.

 Not all HIV-infected persons have symptomatic disease; some live a healthy symptom-free life for years.

 Acquired immune deficiency syndrome (AIDS) is a group of disorders characterized by a profound cell- mediated immunodeficiency consequential to irreversible suppression of T lymphocytes by HIV and associated with opportunistic infection, malignancies and autoimmune disorders.

 AIDS-defining illnesses are characterized by a CD4 lymphocyte count below 200 x 106/l, oropharyngeal candidiasis and hairy leukoplakia.

 Two major subtypes of HIV are known: HIV-1 is more prevalent than HIV-2; both subtypes have similar biological properties.

 The structure of HIV is characterized by an envelope containing virus-specific ‘coat’ proteins (e.g., glycoproteins, gp120); three core proteins (e.g., p24); a genome of RNA; and two molecules of an enzyme, reverse transcriptase.

 HIV is destroyed by heat (autoclave and hot-air oven) and disinfectants (e.g., 2% glutaraldehyde and hypochlorite).

 HIV is transmitted by blood-to-blood contact, sexual contact and perinatally.

 HIV is unlikely to be transmitted by saliva as it is infrequently present and in very low titres in saliva, and salivary immunoglobulin A (IgA) and serine protease inhibitors

(salivary leukocyte protease inhibitor [SLPI]) neutralize the virus.

 Noteworthy opportunistic infections and neoplasms in AIDS include pneumocystis pneumonia (PCP), toxoplasmosis, atypical mycobacteriosis, candidiasis, herpesvirus infections and Kaposi’s sarcoma.

 The earliest indicators of HIV infection may manifest in the oral cavity, and the more common of these are oral candidiasis, hairy leukoplakia, Kaposi’s sarcoma, recurrent ulcers and cervical lymphadenopathy.

 Diagnosis of HIV is performed by screening with enzyme- linked immunosorbent assay (ELISA) tests (agglutination test for serum antibodies) and subsequent confirmation by Western blot assay.

 The two main groups of drugs used to suppress HIV proliferation are the reverse transcriptase inhibitors (nucleoside and non-nucleoside) and protease inhibitors.

 Barrier contraceptives are the mainstay of HIV prevention for the foreseeable future.

 A compromised host is a person whose normal defence mechanisms are impaired, making the individual more susceptible to infection.

 Immunodeficiency disease can be either primary (developmental or genetically determined), which is rare, or secondary, due to procedures such as irradiation and cytotoxic drug therapy.

 The chronic dryness of the mucosa in xerostomia leads to caries, periodontal diseases, candidiasis and ascending (bacterial) sialadenitis.

Review questions (answers on p. 367)

Please indicate which answers are true, and which are false.

30.1 Human immunodeficiency virus (HIV):

A. genome consists of two identical single-stranded RNA molecules

B. envelope proteins undergo continuous structural changes

C. p24 is an important coat protein

D. possesses reverse transcriptase activity

E. can survive in the saliva of HIV-infected individuals

30.2 HIV is likely to be transmitted when:

A. kissing the cheek of an AIDS patient

B. having unprotected sex with a prostitute

C. an HIV-infected dentist does an amalgam filling on a patient

D. a nurse sustains an injury with a needlestick, disinfected in 5% ethanol for 5 min and previously used for venepuncture of an AIDS patient

E. sharing cutlery in a household with an HIV-infected individual

30.3 Which of the following statements on compromised patient groups are true?

A. mucositis is commonly seen in patients on radiotherapy

B. oral candidiasis is one of the commonest manifestations in compromised persons

C. chronic periodontal disease is seen in leukaemic states

D. appropriate restorative dental procedures must be conducted prior to radiotherapy for oral diseases

E. dysgeusia is a side effect of xerostomia

30.4 A 65-year-old male receives radiotherapy for his nasopharyngeal carcinoma. Indicate which of the following scenario/s is/are likely to be due to this management mode:

A. he loses his sense of smell

B. he has difficulty in wearing his lower full denture

C. his salivary lactobacillus count is likely to rise

D. he has reduced gingival bleeding during tooth-brushing

E. he has swelling of his parotid gland/s

30.5 Which of the following statements on the management of HIV disease are true?

A. the enzyme-linked immunosorbent assay (ELISA) test is more specific for HIV infection than the Western blot

B. highly active antiretroviral therapy (HAART) suppresses the oral manifestations of HIV

C. fluconazole is the antifungal of choice in managing oral candidiasis in HIV disease

D. hairy leukoplakia, due to a herpes group virus, needs to be managed by excision of the lesion

E. combination therapy with reverse transcriptase inhibitors and nucleoside analogues is more effective than monotherapy for treating HIV disease

Further reading

Davies, A. N., & Epstein, J. B. (2010). Oral complications of cancer and its management. Oxford: OUP.

EC Clearinghouse on Oral Problems Related to HIV Infection and WHO Collaborating Centre on Oral Manifestations of Immunodeficiency Virus. (1993). Classification and diagnostic criteria for oral lesions in HIV infection. Journal of Oral Pathology and Medicine, 22, 289-291.

Lewis, M. A. O., & Jordan, R. C. K. (2004). A colour handbook of oral medicine. London: Manson Publishing.

Pillay, D., Geretti, A. M., & Weiss, R. A. (2009). Human immunodeficiency viruses. In A. J. Zuckerman, J. E. Banatvala, P. Griffith, et al. (Eds.), Principles and practice of clinical virology (6th ed.). Ch. 38. Chichester: John Wiley.

Samaranayake, L. P. (1992). Oral mycoses in human immunodeficiency virus infection: A review. Oral Surgery, Oral Medicine, Oral Pathology, 73, 171-180.

Samaranayake, L. P., & Pindborg, J. J. (1989). Hairy leukoplakia. British Medical Journal, 298, 270-271.

Samaranayake, L. P., & Scully, C. (1989). Oral candidosis in HIV infection. Lancet, ii, 1491-1492.

Scully, C., & Cawson, R. A. (2010). Medical problems in dentistry (6th ed.). London: Churchill Livingstone.

Sepkowitz, K. A. (2001). AIDS - The first twenty years. New England Journal of Medicine, 344, 1764-1768.

Tsang, C., & Samaranayake, L. P. (2010). Immune reconstitution inflammatory syndrome (IRIS) after highly active antiretroviral therapy: A review. Oral Diseases, 16, 248-256.



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