Generalized cutaneous candidiasis manifests as a diffuse eruption over the trunk, thorax, and extremities. Patients have a history of generalized pruritus with increased severity in the genitocrural folds, anal region, axillae, hands, and feet. Physical examination reveals a widespread rash that begins as individual vesicles and spreads into large confluent areas.

I ntertrigo affects any site where skin surfaces are in close proximity, providing a warm, moist environment. A red pruritic rash develops, beginning with vesiculopustules, and enlarging to bullae, which then rupture causing maceration and fissuring. The area involved typically has a scalloped border, with a white rim, consisting of necrotic epidermis that surrounds the erythematous macerated base. Satellite lesions are frequently found. These may coalesce and extend into larger lesions. Candida folliculitis is predominantly found in hair follicles and rarely becomes extensive. Paronychia and onychomycosis are frequently associated with immersion of the hands in water, especially in patients with diabetes mellitus. These patients usually have a history of a painful and erythematous area around and underneath the nails and nail beds.

Chronic mucocutaneous candidiasis describes a unique group of individuals with Candida infections of the skin, hair, nails, and mucous membranes that tend to have a protracted and persistent course. Most infections begin in infancy or the first two decades of life; whereas onset in people older than 30 years is rare. These chronic and recurrent infections frequently result in a disfiguring form called Candida granuloma. Most patients survive for long periods and rarely experience disseminated fungal infections. Chronic mucocutaneous candidiasis is frequently associated with multiple endocrinopathies. Examination reveals disfiguring lesions of the face, scalp, hands, and nails occasionally associated with oral thrush and vitiligo.

Oropharyngeal candidiasis (OPC) occurs in association with serious underlying conditions such as diabetes, leukemia, neoplasia, corticosteroid use, antimicrobial therapy, radiation therapy, dentures, and human immunodeficiency virus ( HIV) infection. Persistent OPC in infants may be the first manifestation of childhood AIDS or chronic mucocutaneous candidiasis. Samonis et al. reported that 28 % of cancer patients not receiving antifungal prophylaxis developed OPC [15]. In a similar immunocompromised, hospitalized population, Yeo et al. observed OPC in 57 % of patients [16].

In the past, approximately 80–90 % of patients with HIV infection developed OPC at some stage of their disease. The presence of OPC should alert the physician to the possibility of underlying HIV infection. Untreated, 60 % of HIV-infected patients develop an AIDS-related infection or Kaposi’s sarcoma within 2 years of the appearance of OPC. Many AIDS patients experience recurrent episodes of OPC and esophageal candidiasis as HIV progresses, and multiple courses of antifungals administered may contribute to the development of antifungal resistance. Antifungal agents are less effective and take longer to achieve a clinical response in HIV-positive patients than in cancer patients. There has been a significant increase in the incidence of non-albicans Candida recovered from HIV-positive patients.

C. albicans remains the most common species responsible for OPC (80–90 %). C. albicans adheres better in vitro to epithelial cells than non-albicans Candida.

The manifestations of OPC (commonly called thrush) vary significantly, from none to a sore, painful mouth, burning tongue, and dysphagia. Frequently, patients with severe objective (examination) changes are asymptomatic. Clinical signs include a diffuse erythema with white patches (pseudomembranous) that appear as discrete lesions on the surfaces of the mucosa, throat, tongue, and gums. With some difficulty, the plaques can be wiped off, revealing a raw, erythematous, and sometimes bleeding base. OPC impairs quality of life and results in a reduction in fluid or food intake. The most serious complication of untreated OPC is extension to the esophagus. Fungemia and disseminated candidiasis are uncommon.

Chronic atrophic stomatitis or denture stomatitis is a very common form of OPC, with soreness and burning of the mouth. Characteristic signs are chronic erythema and edema of the portion of the palate that comes into contact with dentures. Denture stomatitis is found in 24–60 % of denture wearers and is more frequent in women than in men. Notably, C. glabrata has been identified in 15–30 % of all cultures, a higher prevalence than generally found in the mouth. Angular cheilitis ( perlèche), also called cheilosis, is characterized by soreness, erythema, and fissuring at the corners of the mouth. Chronic hyperplastic candidiasis ( Candida leukoplakia) produces oral white patches, or leukoplakia, that are discrete, transparent-to-whitish, raised lesions of variable sizes found on the inner surface of the cheeks and, less frequently, on the tongue. Midline glossitis (median rhomboid glossitis, acute atrophic stomatitis) refers to symmetrical lesions of the center dorsum of the tongue characterized by loss of papillae and erythema.

Candida esophagitis occurs in predisposed individuals. C. albicans is the most common cause. The prevalence of Candida esophagitis increased during the first two decades of the AIDS epidemic and with increased numbers of transplant, cancer, and severely immunocompromised patients.

Esophageal candidiasis in an HIV-infected patient may be the first manifestation of AIDS. Candida esophagitis tends to occur later in the natural history of HIV infection and almost invariably at a much lower CD4 count. In cancer patients, factors predisposing to esophagitis include recent exposure to radiation, cytotoxic chemotherapy, antibiotic and corticosteroid therapy, and neutropenia. Clinical features include dysphagia, odynophagia, and retrosternal pain. Constitutional findings, including fever, occur only occasionally. Rarely, epigastric pain is the dominant symptom. Although esophagitis may occur as an extension of OPC, in more than two thirds of published reports, the esophagus was the only site involved; more often, infection involved the distal two thirds of the esophagus. Candida esophagitis in AIDS patients may occur in the absence of symptoms despite extensive objective esophageal involvement. Kodsi classified Candida esophagitis on the basis of its endoscopic appearance [17]. Type I cases refer to a few white or beige plaques up to 2 mm in diameter. Type II plaques are larger and more numerous. In the milder grades, plaques may be hyperemic or edematous, but there is no ulceration. Type III plaques may be confluent, linear, nodular, and elevated, with hyperemia and frank ulceration, and type IV plaques, additionally, have increased friability of the mucosa and occasional narrowing of the lumen. Uncommon complications of esophagitis include perforation, aortic-esophageal fistula formation, and rarely, candidemia or bacteremia.

A reliable diagnosis can only be made by histologic evidence of tissue invasion in biopsy material. Nevertheless, antifungal therapy is frequently initiated empirically with minimal criteria in a high-risk patient. The mere presence of Candida within an esophageal lesion as established by brushings, smear, or culture, does not provide sufficient evidence to distinguish Candida as a commensal from Candida as the responsible invasive pathogen.

Radiographic studies have been replaced by endoscopy, which not only provides a rapid and highly sensitive diagnosis but also is the only reliable method of differentiating among the various causes of esophagitis. The characteristic endoscopic appearance is described as yellow–white plaques on an erythematous background, with varying degrees of ulceration. Differential diagnosis includes radiation esophagitis, reflux esophagitis, cytomegalovirus or herpes simplex virus infection. In the AIDS patient, it is not uncommon to identify more than one etiologic agent causing esophagitis.

Laryngeal candidiasis is seen primarily in HIV-infected patients and occasionally in those with hematologic malignancies. The patient presents with a sore throat and hoarseness, and the diagnosis is made by direct or indirect laryngoscopy.

Candida tracheobronchitis is a rare form of candidiasis seen in HIV-positive or severely immunocompromised subjects, complaining of fever, productive cough, and shortness of breath. Physical examination reveals dyspnea and scattered rhonchi. The diagnosis generally is made during bronchoscopy.

Candida pneumonia is also a rare form of candidiasis. The most common form of infection appears to be multiple lung abscesses due to the hematogenous dissemination of Candida. As there may be a high degree of colonization and isolation of Candida from the upper respiratory tract, diagnosis requires the visualization of Candida invasion on histopathology. Patient history usually reveals similar risk factors for disseminated candidiasis, and patients complain of shortness of breath, cough, and fever. Sputum or endotracheal secretions positive for Candida usually indicate upper respiratory tract colonization, have low-predictive value for pneumonia, and unfortunately are incorrectly used as a pretext for initiating antifungal therapy.

In the USA, Candida vaginitis is the second most common vaginal infection. During the childbearing years, 75 % of women experience at least one episode of vulvovaginal candidiasis (VVC), and 40–50 % of these women experience a second episode. A small subpopulation of women experiences repeated, recurrent episodes of Candida vaginitis. Candida may be isolated from the genital tract of about 10–20 % of asymptomatic, healthy women of childbearing age.

Candida vaginitis can be classified as complicated or uncomplicated, depending on factors such as severity and frequency of infection and the causative Candida species (Table 8.2). Increased rates of asymptomatic vaginal colonization with Candida and Candida vaginitis are seen in pregnancy (30–40 %), with the use of oral contraceptives with a high-estrogen content, and in uncontrolled diabetes mellitus. The hormonal dependence of the infection is illustrated by the fact that Candida is seldom isolated from premenarchal girls, and the prevalence of Candida vaginitis is lower after menopause, except in women taking hormone replacement therapy. Other factors include corticosteroid and antimicrobial therapy, the use of an intrauterine device, high frequency of coitus, and refined-sugar eating binges. Recently, an increased frequency of mycotic vulvovaginal infections in type 2 diabetics receiving sodium glucose cotransporter 2 (SGLT2) inhibitors especially non-albicans Candida spp. has been reported.

Vulvar pruritus is the most common symptom of VVC and is present in most symptomatic patients. Vaginal discharge is often minimal and occasionally absent. Although described as being typically “cottage cheese like” in character, the discharge may vary from watery to homogeneously thick. Vaginal soreness, irritation, vulvar burning, dyspareunia, and external dysuria are common. Malodorous discharge is characteristically absent. Typically, symptoms are exacerbated during the week before menses, while the onset of menstrual flow frequently brings some relief.

Examination reveals erythema and swelling of the labia and vulva, often with discrete pustulopapular peripheral lesions. The cervix is normal. Vaginal mucosal erythema with adherent whitish discharge is typically present.

In most symptomatic patients, VVC is readily diagnosed by microscopic examination of vaginal secretions. A wet mount of saline preparation has a sensitivity of only 40–60 %. A 10 % potassium hydroxide preparation (KOH) is more sensitive in diagnosing the presence of budding yeast. Patients with Candida vaginitis have a normal vaginal pH (4.0 to 4.5). A pH of more than 4.5 suggests bacterial vaginosis, trichomoniasis, or mixed infection. Routine cultures are unnecessary; but in suspicious cases with negative microscopy cases, vaginal culture should be performed. Although vaginal culture is the most sensitive method available for detecting Candida, a positive culture does not necessarily indicate that Candida is responsible for the vaginal symptoms.

Candiduria is rare in, otherwise, healthy people. Although epidemiologic studies have documented candiduria in approximately 10 % of individuals sampled, many of these culture results reverted to negative when a clean-catch technique was used. The incidence of fungal urinary tract infections (UTIs), specifically candiduria, has dramatically increased recently, especially among patients with indwelling urinary catheters.

Platt et al. reported that 26.5 % of all UTIs related to indwelling catheters were caused by fungi. Candida are the organisms most frequently isolated from the urine samples of patients in surgical ICUs, and 10–15 % of nosocomial UTIs are caused by Candida [18, 19].

Diabetes mellitus may predispose patients to candiduria by enhancing Candida colonization of the vulvovestibular area (in women), by enhancing urinary fungal growth in the presence of glycosuria, lowering host resistance to invasion by fungi as a consequence of impaired phagocytic activity, and promoting stasis of urine in those with neurogenic bladder.

Antibiotics also increase colonization of the GI tract by Candida, which are normally present in ~ 30 % of immunocompetent adults. In patients receiving antibiotics, colonization rates approach 100 %. Candiduria is almost invariably preceded by bacteriuria. Indwelling urinary catheters serve as a portal of entry for microorganisms into the urinary drainage system. Other risk factors include the extremes of age, female sex, use of immunosuppressive agents, venous catheters, interruption of urine flow, radiation therapy, and genitourinary tuberculosis.

In a large multicenter study by Kauffman et al., C. albicans was found in 51.8 % of 861 patients with funguria. The second most common pathogen (134 patients) was C. glabrata [20]. Other non-albicans Candida are also very common and far more prevalent than in other sites (i.e., oropharynx and vagina), possibly as a function of urine composition and pH selectivity for non-albicans species. In approximately 10 % of patients, more than one species of Candida are found simultaneously.

Ascending infection is, by far, the most common route for infection of the bladder. It occurs more often in women because of a shorter urethra and frequent vulvovestibular colonization with Candida (10–35 %). Ascending infection that originates in the bladder can infrequently lead to infection of the upper urinary tract, especially if vesicoureteral reflux or obstruction of urinary flow occurs. This may eventually result in acute pyelonephritis and, rarely, candidemia. A fungus ball consisting of yeast, hyphal elements, epithelial and inflammatory cells, and, sometimes, renal medullary tissue, secondary to papillary necrosis, may complicate ascending or descending infections.

Hematogenous spread is the most common route for renal infection (i.e., renal candidiasis). Candida have a tropism for the kidneys; one study revealed that 90 % of patients with fatal disseminated candidiasis had renal involvement at autopsy. Frequently, when renal candidiasis is suspected, blood cultures are no longer positive. Patients with renal candidiasis usually have no urinary tract symptoms.

The finding of Candida organisms in the urine may represent contamination, colonization of the drainage device, or infection. Contamination of a urine specimen is common, especially with suboptimal urine collection from a catheterized patient or from a woman who has heavy yeast colonization of the vulvovestibular area. Given the capacity of yeast to grow in urine, small numbers of yeast cells that migrate into the collected urine sample may multiply quickly. Therefore, high colony counts could be the result of yeast contamination or colonization. Colonization usually refers to the asymptomatic adherence and settlement of yeast, usually on drainage catheters or other foreign bodies in the urinary tract (i.e., stents and nephrostomy tubes), and it may result in a high concentration of the organisms on urine culture. Simply culturing the organism does not imply clinical significance, regardless of the concentration of organisms in the urine. In the asymptomatic patient, candiduria almost always represents colonization, and elimination of underlying risk factors, such as indwelling catheter, is frequently adequate to eradicate candiduria [20]. Diagnostic tests on urine often are not helpful in differentiating colonization from infection or identifying site of infection.

Infection is caused by superficial or deep-tissue invasion. Kozinn showed that colony counts of > 10⁴ colony-forming units (cfu)/ml of urine were associated with infection in patients without indwelling urinary catheters, although clinically significant renal candidiasis has been reported with colony counts of 10³ cfu/ml of urine [21]. Pyuria supports the diagnosis of infection in patients with a urinary catheter, but can result from mechanical injury of the bladder mucosa by the catheter or from coexistent bacteriuria. In summary, absence of pyuria and low colony counts tend to rule out Candida infection, but the low specificity of pyuria and counts > 10³ cfu/ml require that results be interpreted in their clinical context. The number of yeast cells in urine has little value in localizing the anatomical level of infection. Rarely, a granular cast containing Candida hyphal elements is found in urine, allowing localization of the infection to the renal parenchyma. Declining renal function suggests urinary obstruction or renal invasion. For candiduria patients with sepsis, it is not only necessary to obtain blood cultures but also, given the frequency with which obstruction and stasis coexist, essential to perform radiographic visualization of the upper tract. Any febrile patient for whom therapy for candiduria is considered necessary should be investigated for the anatomic source of candiduria. In contrast, patients without sepsis require no additional studies unless candiduria persists after the removal of catheters.

Candiduria is most often asymptomatic, usually in hospitalized or nursing home patients with indwelling catheters. These patients usually show none of the signs or symptoms associated with UTI. Symptomatic Candida cystitis is uncommon. Cystoscopy, although rarely indicated, reveals soft, pearly white, elevated patches with friable mucosa underneath and hyperemia of the bladder mucosa. Emphysematous cystitis is a rare complication of lower UTI, as is prostatic abscess and epididymal orchitis.

Upper UTIs present with fever, leukocytosis, and costovertebral angle tenderness, indistinguishable from bacterial pyelonephritis and urosepsis. Ascending infection almost invariably occurs in the presence of urinary obstruction and stasis, especially in patients with diabetes or nephrolithiasis.

A major complication of upper UTI is obstruction caused by fungus balls (bezoars), which can be visualized on ultrasonography. Renal colic may occur with the passage of fungal “stones,” which are actually portions of these fungus balls.

Patients with hematogenous seeding of the kidneys caused by candidemia may present with high fever, hemodynamic instability, and variable renal insufficiency. Blood culture results are positive for Candida in half of these patients. Retinal or skin involvement may suggest dissemination, but candiduria and a decline in renal function are often the only clues to systemic candidiasis in a febrile, high-risk patient.

Candida infection has been increasingly recognized as a cause of abdominal sepsis and is associated with a high mortality. Peritoneal contamination with Candida follows either spontaneous GI perforation or surgical opening of the gut. However, after contaminating the peritoneal cavity, Candida organisms do not inevitably result in peritonitis and clinical infection. Risk factors for peritonitis include recent or concomitant antimicrobial therapy, inoculum size, and acute pancreatitis. Translocation of Candida across the intact intestinal mucosa has been shown experimentally in animals and in a volunteer. Additional risk factors for invasive candidiasis include diabetes, malnutrition, ischemia, hyperalimentation, neoplasia, and multiple abdominal surgeries. Pancreatic transplantation, especially with enteric drainage, is associated with intra-abdominal Candida abscess formation. Candida have a unique affinity for the inflamed pancreas, resulting in intrapancreatic abscesses or infecting accompanying pseudocysts. In Candida peritonitis, Candida usually remain localized to the peritoneal cavity, with the incidence of dissemination at about 25 %.

The clinical significance of Candida isolated from the peritoneal cavity during or after surgery has been controversial. Several earlier studies concluded that a positive culture did not require antifungal therapy. Calandra et al., in a review of Candida isolates from the peritoneal cavity, determined that Candida caused intra-abdominal infection in 19 of 49 (39 %) patients [22]. In 61 % of patients, Candida isolation occurred without signs of peritonitis. Accordingly, in each patient, clinicians should consider the clinical signs of infection and other risk factors when deciding whether to initiate antifungal therapy.

Candida peritonitis as a complication of continuous ambulatory peritoneal dialysis (CAPD) is more common, but it infrequently results in positive blood cultures or hematogenous dissemination. In a series of CAPD patients followed for 5 years, fungal peritonitis, most commonly due to Candida, accounted for 7 % of episodes of peritonitis. Seventeen cases of fungal peritonitis were reported, with eight associated deaths. Few risk factors have emerged except for recent hospitalization, previous episodes of peritonitis, and antibacterial therapy. Clinically, fungal peritonitis cannot be differentiated from bacterial peritonitis except by Gram stain and culture of dialysate.

Yeast in the bile is not uncommon, especially after biliary surgery, and has the same significance as asymptomatic bactibilia (i.e., colonization only); however, Candida is an infrequent cause of cholecystitis and cholangitis. Other risk factors include diabetes, immunosuppression, abdominal malignancy, and the use of biliary stents. Biliary infection is usually polymicrobial, and Candida is a pathogen that should not be ignored when isolated.

Osteomyelitis may present weeks or months after the causal candidemic episode; therefore, at presentation, blood cultures are usually negative and radiologic findings nonspecific. Diagnosis usually requires a bone biopsy.

Occasionally, postoperative wound infections may spread to contiguous bone such as the sternum and vertebrae. Regardless of the source, manifestations resemble bacterial infection, but run a more insidious course, with a significant delay in diagnosis.

Candida arthritis generally represents a complication of hematogenous candidiasis and rarely follows local trauma, surgery, or intra-articular injections. Patients with underlying joint disease (e.g., rheumatoid arthritis, prosthetic joints) are at increased risk. Candida arthritis can occur in any joint, is usually monoarticular (knee), but has been reported to effect multiple joints in up to 25 % of cases. Infection resembles bacterial septic arthritis, but chronic infection often develops with secondary bone involvement because of the delay in diagnosis and suboptimal treatment.

Clinical presentation of candidemia varies from fever alone and absence of any organ-specific manifestations to a wide spectrum of manifestations, including fulminant sepsis. Accordingly, acute candidemia is indistinguishable from bacterial sepsis and septic shock. In general, there are no specific clinical features associated with individual Candida species.

Candidemia may also present with manifestations of systemic and invasive metastatic candidiasis; although when these occur, blood cultures have frequently become negative. Accordingly, candidemia is a marker, although insensitive, of deep invasive candidiasis. Only 50 % of patients with disseminated candidiasis will have positive blood cultures, and an antemortem diagnosis is even lower (15–40 %). Dissemination to multiple organs may not only occur with candidemia, especially to the kidneys, eyes, brain, myocardium, liver, and spleen in leukemia patients, but infection can also involve the lungs, skin, vertebral column, and endocardium.

The possibility of asymptomatic disseminated infection drives the treatment principles of candidemia. Transient candidemia can occur from any source, but most often follows intravascular catheter infection, with prompt resolution of candidemia following catheter removal. Prolonged candidemia, especially when blood cultures remain persistently positive on appropriate antifungal treatment, suggests a persistent focus or source (e.g., intravascular catheter, abscess, suppurative thrombophlebitis, endocarditis, severe neutropenia), or antifungal resistance, which albeit rare, is more common with some of the non-albicans Candida. When candidemia is diagnosed, a general physical examination rarely reveals clinical signs of dissemination; but a thorough examination, including a dilated funduscopic examination, is mandatory. The crude mortality rate reported in patients with candidemia ranges from 40–60 %, with an attributable mortality of 38 %, exceeding that of most bacteremias. A 50 % reduction in national mortality rates for invasive candidiasis since 1989 was reported after a steady increase in mortality in the previous decades, reaching 0.62 death/100,000 population. The decrease in mortality, despite increased invasive disease, may be related to increased awareness, earlier diagnosis, and increased therapeutic options, primarily fluconazole and echinocandins.