Chapter 28 Candida in HIV infection

Epidemiology

Candidiasis is caused by fungi of the Candida species, which are yeasts that are ubiquitous in the environment. Candida species are common human commensal organisms on skin and mucous membranes; between 30% and 80% of adults and children are colonized with Candida species [1, 2]. The point prevalence of carriage is higher in at-risk groups, such as cancer patients and HIV-infected persons [3–5]. In general, such colonization with Candida does not cause infection. The primary defense mechanisms involved in protection against local infection with Candida involve the cell-mediated immune system. Progressive loss of T-cell function associated with HIV disease leads to an increased risk of direct local invasion of Candida and localized infection. Other host factors important in the defense against Candida infections include blood group secretor status, salivary flow rates, epithelial barrier, antimicrobial constituents of saliva, and the presence of normal bacterial flora. Several studies suggest that HIV infection is associated with impairment in a number of these local mucosal defense mechanisms.

Mucosal candidiasis is a common opportunistic infection in HIV-infected individuals. Oropharyngeal candidiasis (OPC) usually occurs with low CD4 counts, but tends to be one of the earliest opportunistic infections and may be seen in patients with CD4 counts <200/mm³. The finding of oropharyngeal candidiasis should never be dismissed in an HIV-infected patient; it indicates progressive immune deficiency and should prompt the institution of effective antiretroviral therapy.

Prior to the era of highly active antiretroviral therapy (HAART, or ART), between 50 and 75% of HIV-infected individuals developed at least one episode of mucosal candidiasis. Recurrent episodes are frequent with progressive immune deficiency. The incidence has declined since the introduction of ART in the late 1990s. Higher HIV viral load is significantly associated with increased oral or vaginal colonization and candidiasis, an association that has been reduced by ART [6]. However, in parts of the world where ART is not widely available, mucosal candidiasis continues to represent a significant cause of morbidity. Esophageal candidiasis affects between 10% and 20% of patients with AIDS. Candida infection is the most common cause of esophageal disease in persons with HIV infection.

The epidemiology of mucocutaneous candidiasis has changed in the last 10 years primarily because of two factors. The first is the widespread use of antifungal agents, particularly the azoles. Continuous use of azoles has led to a decline in the prevalence of mucosal candidiasis but also led to the emergence of refractory infections caused by azole-resistant Candida. The second factor influencing Candida epidemiology in AIDS has been the introduction of potent ART, which has resulted in a significant decline in the incidence of all opportunistic illnesses, including mucosal candidiasis. It is reasonable to expect that the incidence of mucocutaneous candidiasis in HIV-infected patients will continue to decline as more patients receive effective ART.

The majority of cases of candidiasis in the setting of HIV infection are confined to mucosal surfaces i.e. oropharyngeal, esophageal, and vulvovaginal; systemic candidiasis is rare and usually occurs in patients with advanced HIV/AIDS (often in the setting of neutropenia) or occurs as a result of nosocomial acquisition. While oropharyngeal and esophageal candidiasis are clearly HIV-associated illnesses, it is likely that vulvovaginal candidiasis (VVC) is not. HIV-seropositive women have a higher prevalence of vaginal colonization with Candida compared with seronegative women. However, the incidence of vulvovaginal candidiasis is unrelated to HIV serostatus and tends to reflect other risk factors for vulvovaginal Candida infection such as sexual activity and socioeconomic status. The prevalence of vulvovaginal disease is also independent of CD4 count and does not increase with advancing immunodeficiency. However, the severity and frequency of recurrence of vulvovaginal candidiasis may be linked to progressive HIV infection, and, as a consequence, this remains an important source of morbidity in infected women. This may indicate a difference in pathogenesis of Candidal infection at the two sites, oropharynx and vagina [7].

The most common causative organism is Candida albicans [8], found in over 90% of isolates from patients with their first episode of oropharyngeal candidiasis. In patients with recurrent disease, the same strain causes the relapse in approximately half of cases, but other strains or species may also be implicated. The majority of disease is caused by organisms that are part of the normal flora of an individual, although rare cases of person-to-person transmission have been documented. In patients with prolonged or recurrent antifungal use, non-albicans species with different antimicrobial susceptibilities become more commonly isolated. These include C. glabrata, C. tropicalis, C. krusei, and C. dubliniensis [9, 10]. Some of these species are more likely to be associated with decreased susceptibility to azole antifungals [11].

Clinical Manifestations

Oropharyngeal candidiasis

Almost all patients with OPC are symptomatic, complaining of a sore mouth or oropharyngeal pain with swallowing. On inspection, OPC is usually associated with visible creamy white plaques on the tongue, hard or soft palate. If scraped, these plaques have an erythematous base (this is the pseudomembranous form of OPC, often referred to as thrush). Other clinical manifestations include angular cheilitis, which is a non-specific inflammation of the angles of the mouth, and acute or chronic atrophic candidiasis, which can present as erythematous tongue and/or thinning of the mucous membranes. Although usually associated with mild morbidity, OPC can be clinically significant. Severe OPC can interfere with the administration of medications and adequate nutritional intake, and may spread to the esophagus.

The differential diagnosis of oropharyngeal candidiasis includes:

1. Oral hairy leukoplakia (OHL). OHL is characterized by raised white lesions in the oral mucosa, usually found on the sides of the tongue. It is associated with herpes viruses in the epithelial cells, particularly Epstein–Barr virus (EBV). It can be differentiated from candidiasis by inability to scrape off the plaque or by lack of response to antifungal therapy. Antiviral therapy with acyclovir can be used for treatment, although specific antiviral treatment is not usually required as the condition is typically asymptomatic. OHL is an indication for ART.

2. Oral ulcers. Extensive oral ulceration can be seen in the setting of HIV infection. It has many causes, including herpes simplex virus (HSV) type I and II, cytomegalovirus (CMV), drug toxicities (e.g. Stevens–Johnson syndrome due to co-trimoxazole or antiretrovirals). However, the most common cause is idiopathic aphthous ulceration. Patients typically have single or multiple discrete ulcers that are usually painful and may coalesce or become secondarily infected. Treatment involves identifying the cause and discontinuing the causative agent if relevant. In the case of viral ulceration, systemic antivirals such as acyclovir may be useful. With aphthous ulceration, topical steroids or analgesic mouthwashes are helpful, and oral thalidomide therapy has been shown to be effective in severe cases [12].

3. Gingivitis and periodontitis. Severe oral cavity disease has been seen in HIV infection. It usually presents with painful bleeding gums, halitosis, and dental loosening. There may be ulceration of gums. It is caused by mixed aerobic and anaerobic infection and responds to topical agents; systemic therapy with metronidazole may be required.

4. Kaposi’s sarcoma. When present in the oral cavity, the typical purple lesions of KS are usually seen on the palate. If large, the lesions may ulcerate due to local trauma. Biopsy establishes the diagnosis.

5. Non-Hodgkin’s lymphoma can cause oral cavity disease in HIV patients. It may present as a mass lesion, tonsillar in origin, or as ulceration of the mucosa. Biopsy establishes the diagnosis.

Esophageal candidiasis

Patients are usually symptomatic with dysphagia and/or odynophagia. Retrosternal pain or discomfort may be present. There may or may not be concurrent oropharyngeal involvement. Severe symptoms can lead to considerable difficulty in eating or swallowing liquids, which can interfere with nutrition or hydration. In a patient with OPC, complaints of swallowing difficulty or retrosternal symptoms, should prompt a high clinical suspicion of esophageal candidiasis, and empiric antifungal therapy should be initiated. In atypical cases or those refractory to empiric antifungal therapy, direct visualization of the esophagus by endoscopy is the best way to make the diagnosis. The epithelial lining of the esophagus is coated in a pseudomembrane consisting of yeasts, epithelial cells, leukocytes, and necrotic debris. Erosions or ulcers may be seen. An experienced endoscopist will often make the diagnosis on macroscopic appearance. Definitive diagnosis is made by brushings or biopsy of the mucosa. The differential diagnosis includes viral esophagitis caused by CMV or HSV types I and II and severe aphthous ulceration. A helpful clinical clue in differentiating the different infectious causes of esophagitis in HIV-infected patients is that esophagitis due to C. albicans often results in complaints of food ‘sticking in the throat,’ whereas esophagitis due to HSV or CMV more often produces complaints of actual pain with swallowing.

Vulvovaginal candidiasis

As noted previously, this is a common clinical syndrome in women irrespective of HIV status or immune function. There are many additional predisposing factors to the development of genital Candida infection, including diabetes, oral contraceptive use, pregnancy, and systemic antibiotic therapy.

VVC generally presents with itching, a vaginal discharge (which may be watery or thick), vaginal erythema with adherent white discharge, dyspareunia, dysuria, and erythema and swelling of the labia and vulva. The cervix usually appears normal. Initial episodes tend to be uncomplicated, mild to moderate in severity, and sporadic, usually caused by C. albicans. More complicated VVC tends to occur in more immunocompromised hosts, is often recurrent, and is more likely to be caused by non-albicans species.

Unprotected intercourse with a partner with VVC may lead to Candida balanitis in the male partner, manifested by pruritic, erythematous patches on the glans penis.

Disseminated candidiasis and candidemia

In HIV-infected individuals, this is a rare and usually late event, typically occurring in patients with advanced immunosuppression. It is most often a hospital-acquired infection, with non-albicans Candida playing a significant role in pathogenesis. There has been a significant reduction in the incidence of nosocomial candidemia in HIV-infected patients in the post-HAART era [13]. Risk factors are those of nosocomial acquisition, including presence of a central venous catheter, use of gastric acid suppressants, nasogastric tubes, antibiotics, ICU admission [14], severe esophageal mucosal disease, advanced AIDS, concomitant opportunistic infections, non-albicans species, and neutropenia. Virtually every body organ can be affected by Candida infection. Involvement of the eyes (endophthalmitis), central nervous system (meningitis [15], encephalitis), and heart (endocarditis) are described but rare in the setting of HIV infection.

Community-acquired candidemia and disseminated candidiasis in HIV is sometimes seen in countries where injection drug users make up a significant proportion of the HIV-infected population. This can present as end-organ disease such as endocarditis, endophthalmitis or skin lesions [16–18].

Diagnosis

The diagnosis of mucosal candidiasis is usually a clinical one. The presence of characteristic symptoms with or without clinical findings in an HIV-infected patient is often enough to warrant treatment. In many ways, this constitutes a therapeutic trial, with lack of response to empiric antifungal therapy prompting further diagnostic testing. Oropharyngeal cultures often demonstrate Candida species but are not diagnostic because colonization is common. The diagnosis of OPC can be confirmed by examining a 10% potassium hydroxide (KOH) slide preparation of a scraping of an active lesion. Pseudohyphae and budding yeast are characteristic findings. Culture is usually not necessary with initial episodes of OPC unless the lesions fail to clear with appropriate antifungal therapy. In patients with poorly responsive OPC, a culture should be obtained to look for drug-resistant yeast or those that respond poorly to certain azoles (e.g. C. krusei or C. glabrata).

The diagnosis of Candida vaginitis is made by the presence of a characteristic clinical appearance and observation of yeast forms on microscopic examination. A KOH preparation from vaginal lesions can confirm the diagnosis of candidiasis and differentiate it from other conditions that can be similar in appearance (e.g. trichomoniasis). Routine fungal cultures are rarely helpful in the absence of KOH-positive lesions because yeasts are normal inhabitants of the vaginal mucosa. A fungal culture should be obtained if a patient fails to respond to standard antifungal therapy to determine whether azole resistance is contributing to the therapeutic failure.

In the microbiology laboratory Candida spp. are relatively easy to culture. They grow rapidly on simple media at 25–37°C. Candida colonies are smooth and creamy white in color on agar plates. Specialized media can differentiate between species by colony color (CHROMagar Candida) and are very useful. Germ tube testing is a relatively quick method of determining whether the organism is Candida albicans or a non-albicans species. Many microbiology laboratories report yeast cultures as either C. albicans or non-albicans species based upon the germ tube test; if specific identification is required, further discussion with the microbiologist is often necessary.

Efforts to develop a standardized reproducible and clinically relevant method of susceptibility testing for yeasts have resulted in development of the NCCLS M27-A2 methodology [19], which has data-driven interpretive breakpoints for susceptibility of Candida spp. to antifungal agents (Table 28.1). Data relating to fluconazole and itraconazole are more readily available than for other antifungals. Susceptibility testing of Candida spp. is not routinely used in most laboratories. The identification of the species is often enough to predict likely antifungal susceptibility, and further testing is not required. However, in the setting of recurrent infection, failure to respond to initial therapy or systemic infection with non-albicans species, susceptibility testing may contribute to clinical decision making and can also be used to support a decision to switch from a parenteral to oral agent. The dose and delivery of the antifungal agent are important in interpreting the data, and host factors play a significant role in the clinical response to a particular agent irrespective of laboratory susceptibility data [20].

Table 28.1 Definition of in vitro resistance for Candida species. Range of MICs (μg/mL)