fungal infections in immunocompromised individuals

CUTANEOUS MYCOLOGY 0733-8635/96 $0.00 + .20

FUNGAL INFECTIONS IN IMMUNOCOMPROMISED

INDIVIDUALS

Marcus A. Conant, MD

The appearance of the acquired immunodeficiency syndrome (AIDS) in 1981 forced clinicians to reevaluate the impact of a compromised immune system on the natural history, clinical appearance, and response to treatment to all infectious agents. This article ex- amines how this reassessment has enhanced our understanding of fungal diseases in the immunocompromised ~ a t i e n t . ~

The pathophysiology of a disease requires a comprehensive understanding of the anat- omy, physiology, and health of the host. Thus, before we can understand the natural history of a fungal infection in an immunocompromised individual, it is essential that we understand that there are multiple mechanisms responsible for immunodeficiency and that each of these mechanisms results in a unique permissiveness for certain fungi.

This examination of the immune system raises the question of the critical defect responsible for mycotic colonization and has allowed us to use this clinical knowledge to stage patients with progressive immunodeficiency. It also raises the fascinating question of why some individuals develop certain fungal diseases and others do not.

The history of a cutaneous or systemic fungal infection in an immunocompromised patient may be quite different from the medical history given by someone with an intact immune system. The physical findings may be

altered by the patient’s inability to respond with a normal inflammatory response to the mycotic pathogen. Laboratory test results must be interpreted in terms of the patient’s basic underlying immunodeficiency, and the response to therapy will clearly be affected by the lack of a normal humoral and cell- mediated response to assist the patient in eliminating the fungal infection.

An immunocompromised patient is obvi- ously at greater risk of succumbing to an infection by an opportunistic pathogen, and profound immunodeficiency is an open invi- tation to new pathogens to attack and invade the immunocompromised patient. Indeed, this has been seen in patients with AIDS.

Finally, a comprehensive understanding of fungal infections in immunocompromised patients focuses our research, for it leads us to the realization that treatment must be di- rected not only at eliminating the fungal pathogen, but at restoring and maintaining the immune system of the host.

THE COMPLEXITY OF IMMUNODEFICIENCIES

Immunodeficiencies may be inherited or acquired, simple or complex, humoral or cell mediated, or a combination of each of these factors. The immunodeficiency may remain

From the Department of Dermatology, University of California Medical Center, San Francisco, San Francisco, California

DERMATOLOGIC CLINICS

VOLUME 14 NUMBER 1 *JANUARY 1996 155

156 CONANT

Table 1. TYPES OF IMMUNODEFICIENCY

Immune System Abnormality Associated Clinical Syndromes

Antibody deficiency (B-cell mediated) Complement abnormality Angioneurotic edema

X-linked hypogammaglobulinemia

Systemic lupus erythematosus Dermatomyositis Leiner’s disease Raynaud’s syndrome Chronic vasculitis

Cytokine abnormalities AIDS Cell-mediated deficiency Chronic mucocutaneous candidiasis Natural killer T-cell deficiency (CD, cells) AIDS Phagocyte and monocyte deficiency Granulocytopenia

Chronic granulomatous disease Chediak-Higashi syndrome Hyper-lgE (Job’s) syndrome Severe combined immunodeficiency syndrome Wiskott-Aldrich syndrome (low levels of IgM) Ataxia-telangiectasia (low levels of IgA, IgE)

Combined B-cell and T-cell deficiency

stable, improve with time, or aggressively de- teriorate immunologic function. Treatment may be partially or completely restorative as in the case of children with defects in humoral immunity treated with high doses of immunoglobulin, or it may be of only partial or transient benefit as in patients with human immunodeficiency virus (HIV) treated with nucleoside reverse transcriptase inhibitors. Inherited diseases may manifest at birth as in cases of combined immunodeficiency syndrome or may not become apparent until the child is older as is seen in ataxia-telangiectasia. Acquired immunodeficiency can result from exposure to environmental toxins, infectious agents, or disease processes such as cancer or be induced iatrogenically by medica- tions.

Immune disorders are commonly divided into humoral abnormalities such as antibody deficiency, complement abnormalities, and defects in cytokine function. Cell-mediated abnormalities include T-cell deficiency, natural killer T-cell (NK cell) abnormality, and monocyte and phagocyte deficiencies. Com- bined immunodeficiency syndrome is charac- terized by both humoral and cell-mediated abnormalities because of both B-cell and T- cell abnormalities (Table 1).

Inherited immunodeficiencies include combined immunodeficiency syndrome, Wiskott- Aldrich syndrome, ataxia-telangiectasia, dyskeratosis congenita (Zinsser-Cole-Engman ~yndrome),’~ and severe combined immunodeficiency syndrome.

Acquired environmentally induced immunodeficiencies can be caused by environ-

mental toxins, malnutrition, and thermal burns.

Infectious agents causing immunodeficiency include a variety of viral diseases, including measles, which can cause a transient immunodeficiency and, of course, AIDS caused by HIV, which causes a progressive and generally fatal immune deficiency state.

Diseases that result in profound immunodeficiency include Hodgkin’s disease and lymphomas. Patients who receive aggressive chemotherapy for the treatment of cancer become immunosuppressed and are at high risk for systemic fungal infections.I2

Iatrogenic causes of immunodeficiency are high doses of corticosteroids, such as those typically administered for temporal arthritis4 and systemic lupus erythematosu~,’~ as well as prolonged treatment with corticosteroids in patients with Wegener’s granulomat~sis~ and other chronic immunologic diseases.

Patients who receive organ transplants, who are immunosuppressed with corticosteroids in conjunction with cyclosporine, con- stitute an additional and growing group of severely immunocompromised patients. Finally, patients profoundly immunosuppressed even for short periods of time, such as bone marrow recipients, are at high risk for systemic fungal infections27 (Table 2).

The precise mechanism of immunosuppres- sion that occurs with each type of immunodeficiency syndrome is understood for some inherited diseases but is certainly not fully understood in the case of AIDS, in many cases of cancer, and in certain types of iatrogenic immunodeficiency. In some instances,

FUNGAL INFECTIONS IN IMMUNOCOMPROMISED INDIVIDUALS 157

Table 2. CAUSES OF IMMUNODEFICIENCY

Inherited Wiskott-Aldrich syndrome

Acquired immunodeficiencies Ataxia-telangiectasia

Environmental Malnutrition, thermal burns Infectious AIDS

Syphilis, measles Malignancies Hodgkin’s disease

Lymphoma Iatrogenic Corticosteroids

Cyclosporine Chemotherapy

immunodeficiencies

the immunodeficiency is a pure defect in one arm of the immune system; in other situations the immunodeficiency may be multifactorial, with aberrations in humoral immunity, cell- mediated immunity, and cytokine produc- tion. A comprehensive understanding of each of these defects should lead to a more precise ability to predict the types of diseases that will be seen with each immunodeficiency condition and to identify those areas of the immune system that need restoration. Ulti- mately, this identification of the critical defect of the immune system will define ”suscep- tibility” of a patient to a particular fungal pathogen.

TYPES OF DISEASES SEEN

There is an unfortunate tendency to discuss the infectious diseases seen in immunodeficient patients without a comprehensive understanding that different types of immunodeficiency are permissive for specific disease states. Candida infections of the mouth are common in patients receiving systemic corticosteroids and are seen commonly in patients infected with HIV. On the other hand, Pneu- rnocystis carinii pneumonia is rare in patients receiving high-dose suppressive corticosteroid therapy, but is extremely ‘common in patients with AIDS.’O, Before prophylaxis with trimethoprim/sulfamethoxazole was in- troduced in 1988 to prevent Pneurnocystis carinii pneumonia, more than 50% of all of the cases of AIDS seen in San Francisco were diagnosed due to pneumocystosis (Table 3). Pneurnocystis carinii is an opportunistic fungal pathogen that commonly invades the lung when the CD, count (helper T-cell count) decreases below 200.23 Pneurnocystis, however, can invade most other organs of the body

Table 3. AIDS CASES BY PRIMARY DIAGNOSIS: SAN FRANCISCO, 1981 TO 1987

Primary Diagnosis Percent

Pneumocystis carinii pneumonia 58.0 Kaposi’s sarcoma 30.2 Disseminated cryptococcal infection 3.1 Candida esophagitis 1.5 Non-Hodgkin’s lymphoma 1.5 Atypical mycobacterial infection 1.3 Cryptosporidiosis 1.3

Toxoplasmosis 0.6 Primary lymphoma of the brain 0.5 Progressive multifocal leukoencephalopathy 0.4 Disseminated herpes simplex virus infection 0.3 Histoplasmosis 0.1 lsosporiasis 0.1 Lymphoid interstitial pneumonia 0.0

Total 100.0

Cytomegalovirus infection 1.2

Data from San Francisco Department of Public Health.

including the intestine, skin, liver, and lymph nodes.

Molluscum contagiosum is commonly seen in patients suffering from the Wiscott-Aldrich syndrome and from various forms of lymphoma. Mollusca are also common in patients infected with HIV but are rare in patients who are chronically immunosuppressed for organ transplantation. Multiple verruca vul- garis of the lower extremities are commonly seen in the immunotransplant patients. Al- though human papillomavirus disease is frequently seen in HIV-infected individuals, multiple warts of the lower extremities rarely occur.

At present, we are just beginning to fully understand all of the interactions that are necessary to orchestrate a fully competent immune system. Deficiencies in one arm of the immune system may cause deficiencies or overcompensation in other arms, which then cause further perturbations throughout the entire system. There has been no concerted effort to plot the frequency of fungal diseases and other infections with each type of immunodeficiency. Such a study would be clearly beneficial to the clinician and might pinpoint the step in the immunodeficiency state that is critical for the appearance of that specific fungal, viral, and bacterial disease.

MEDICAL HISTORY IN THE IMMUNOCOMPROMISED PATIENT

Immunocompromised patients often present with an atypical medical history. Patients

158 CONANT

with seborrheic dermatitis may experience severe facial involvement, with little or no se- borrhea of the scalp. These patients respond to topical corticosteroids as well as topical and systemic antifungal agents such as ketoconazole, fluconazole, and itraconazole. Ces- sation of treatment in the immunocompromised patients almost invariably leads to a recurrence of the cutaneous or systemic fungal infection.6

The immunocompromised patient may present with tinea corporis, tinea cruris, or tinea pedis, but frequently the patient pre- sents with a history of severe pruritus ani, which on examination proves to be a combination of both a fungal and a bacterial infection in a macerated, intertriginous area.

Oral Candida was one of the first diseases recognized in patients infected with HIV and is frequently seen in both the typical pseudo- membranous presentation and the less frequently recognized but equally uncomfort- able erythematous or atrophic form. Both forms can be associated with esophageal candidiasis and indeed with systemic Candida infection.

In women immunocompromised as a result of HIV infection almost 50% present with a history of recurrent and persistent vaginal candidiasis.21 The most common organism is Candida albicans but other species have been seen. Unfortunately, many clinicians do not have a high index of suspicion for immunodeficiency and particularly HIV disease. For this reason, many women presenting with a history of chronic vaginal candidiasis are not offered an HIV test until much later in the course of their disease.

Most patients infected with Cryptococcus neoformans present with CNS symptoms that must be differentiated from toxoplasmosis or lymphomas. Occasionally, patients present with cutaneous Cryptococcus neoformans, which must be differentiated from cutaneous Histoplasma capsulatum and molluscum contagiosum. A biopsy with a periodic acid- Schiff stain reaction will generally establish the diagnosis quickly. Patients with either cryptococcosis or histoplasmosis need to be aggressively managed to arrest the acute infection and to prevent further dissemination. Once the patient has recovered from the ini- tial infection, lifelong prophylaxis is essential to prevent recurrence.

In the immunocompetent patient cryptococcal infection may be limited to a localized pulmonary lesion. In the immunodeficient

patient cryptococcosis may involve the CNS, lung, lymph nodes, skin, adrenal gland, kid- ney, and prostate.

PHYSICAL EXAMINATION IN THE IMMUNOCOMPROMISED PATIENT

Immunocompromised patients may fail to respond to a fungal infection with the normal cell-mediated or humoral reaction that not only limits the fungal infection, but is often responsible for many of the clinical signs.

Patients with seborrheic dermatitis may find the disease-presenting in unusual areas such as the central back or the groin, with little or no involvement of the scalp or face. Patients with tinea pedis may find that the disease extends to the dorsum of the foot rather than remaining in the intertriginous web as one would expect in the immunocompetent patient. Finally, patients with cryptococcal meningitis may experience a severe headache and fever but not have a stiff neck because of the lack of an inflammatory reaction in the menin- ges. Cryptococcal meningitis is generally diagnosed by demonstrating cryptococcal antigen in the spinal fluid and by culture. Budding yeast forms can be seen in up to 82% of the cases. Patients with pulmonary histoplasmosis may have advanced disease before they begin to experience pulmonary symptoms.

Even patients with advanced cases of Pneu- rnocystis may have no physical findings on auscultation of the chest, and their chest ra- diograph may be perfectly normal. Generally, the patient complains of severe fatigue and profound shortness of breath with modest exertion, such as by climbing one flight of stairs. She or he will also show decreased oxygen saturation. If the patient is experiencing a cough, an induced sputum may demon- strate the organism. Often a gallium scan or fiberoptic bronchoscopy is necessary to de- finitively establish the diagnosis.

UNUSUAL PATHOGENS IN IMMUNOCOMPROMISED PATIENTS

Penicillium marneffei' is a dimorphic fungus that occurs normally in the bamboo rat. This disease in immunocompetent and immunocompromised patients was first reported from Thailand. Vithayasai and her colleagues have collected more than 200 cases of penicilliosis in HIV-infected patients. Cutaneous lesions


are generally small umbilicated papules that resemble molluscum contagiosum and could be easily confused with cutaneous Cryptococ- cus neoformans or Histoplasma capsulatum.22, 24

The lesions are often multiple and may ulcer- ate. A smear from one of the cutaneous papules demonstrates the yeast form of Penicil- lium mameffei, and on Wright-Giemsa stain a typical clear central separation is characteris- tic of the yeast.

Cases of Penicillium mameffei invading the nasal pharynx and cervical lymph nodes of the chest and causing marked hepatospleno- megaly have all been described.2* 8, ~ 5 , 26, 28

SKIN DISEASES AS A MARKER OF HIV PROGRESSION

Most patients infected with HIV are profoundly immunosuppressed before they begin to experience clinical symptoms or physical signs. The normal helper T-cell number is between 750 and 2000, with most normal individuals having somewhere in the range of 1500 CD, cells. Infection with HIV results in a profound and progressive loss of CD, cells, and when the CD, number decreases below 500, the patient generally passes from an asymptomatic to a symptomatic state. The symptoms generally experienced include fatigue, fever, nightsweats, weight loss, cough, diarrhea, and vaginal discharge. The findings include a variety of cutaneous diseases such as seborrheic dermatitis, onychomycosis, herpes zoster, oral Candida, vaginal Candida, pru-

ritus ani, oral hairy leukoplakia, molluscum contagiosum, eosinophilic folliculitis, drug eruptions, and resistant herpes simplex (Fig. 1). Generally, the appearance of skin diseases can be used to plot the progression of disease in the HIV-infected immunosuppressed patient: seborrheic dermatitis often is seen when the CD, count is in the range of 400 to 600; onychomycosis is common in patients with more than 400 CD, cells; zoster is seen in the range of 350 to 450, whereas eosinophilic folliculitis is rare in patients with more than 100 CD, cells. These cutaneous diseases, many of which are fungal infections, appear in sequence as the immune system deterio- rates and should alert the clinician to test the patient for HIV infection if the immune status of the patient is not known and to consider altering antiretroviral therapy and infectious disease prophylaxis in the face of clinical evi- dence of disease progression.

Finally, these diseases can be used in the developing world as clinical markers of disease progression when laboratory studies such as CD, counts are prohibitively expen- sive. For example, an adult in the developing world presenting with oral Candida should be offered an HIV test. In all probability, the CD, count will be above 200 and prophylaxis with trimethoprim/sulfamethoxazole will not be necessary. When that patient develops exten- sive molluscum contagiosum infection, then the CD, count is probably in the range where prophylaxis with trimethoprim/sulfamethoxazole will be beneficial in preventing Pneumo- cystis carinii pneumonia.

Figure 1. Opportunistic cutaneous infections over the course of HIV infection.

160 CONANT

Comparative studies from different cultures have shown a wide discrepancy in AIDS-defining diseases in different geo- graphic areaszo The most common cutaneous diseases used to predict disease progression in HIV-infected patients in the United States and Western Europe have been herpes zoster, oral Candida, oral hairy leukoplakia, and molluscum contagiosum. Prospective studies at- tempting to correlate the appearance of cutaneous and systemic fungal diseases with CD, counts in multiple cultures have not yet been initiated.”

Although it is true that most patients begin to experience symptoms and signs of disease progression when the CD, count drops below 500, it is also true that many patients experience decreases in their CD, count to less than 100 cells before any symptoms appear. This observation raises the intriguing question of why some patients experience cutaneous and systemic fungal infections at predictable in- tervals in their disease progression and other patients, who are even more profoundly immunosuppressed, never experience the same diseases.

Why is it that 50% of women experience vaginal Candida when the CD, count drops below 350 and yet all women do not experience this infection when their CD, count is as low as O? Why are some patients bothered with facial seborrheic dermatitis from the time their CD, count drops below 500 until their death, whereas other patients progress through the entire spectrum of HIV disease without experiencing this disease?

RESPONSE TO THERAPY

Immunosuppressed patients almost invariably experience a recurrence of their fungal infection if treatment is not continued indefi- nitely. Seborrheic dermatitis responds quickly to topical corticosteroids and topical ketoconazole. Maintenance with a drying facial cleanser and topical ketoconazole is generally necessary to prevent recurrence.

Onychomycosis is now easily treated with systemic itraconazole. The program of pulse therapy popularized by Hays7 works well in immunosuppressed patients including HIV- positive patients who are profoundly immu- nologically compromised. Because dystrophic nails can be easily confused with onychomycosis, the diagnosis should first be estab- lished by KOH, periodic acid-Schiff, or cul-

ture of the nail. A simple technique is to remove a portion of the nail with rongeurs and submit the nail for histologic examination with a periodic acid-Schiff stain. The derma- tohistopathologist can easily and rapidly make a diagnosis of a mycotic infection. The patient is then treated with itraconazole, 200 mg twice a day for 7 days. This program is repeated each month for 3 months. Tinea corporis, tinea cruris, and tinea pedis can usu- ally be managed with topical antifungal agents such as ketoconazole but lifelong therapy is necessary to prevent recurrence.

Candida of the mouth is easily managed with nystatin vaginal tablets dissolved in the mouth four times a day. This preparation is preferable to nystatin troches and Mycelex troches because of considerably lower cost and the absence of sugar, which can cause dental caries. Once oral Candida has cleared, the patient may be able to prevent colonization of the oral pharynx with good oral hy- giene and aggressive mouth washes two or three times a day. If not, long-term treatment with nystatin vaginal tablets twice a day will be necessary.

If Candida extends into the esophagus, the patient will generally complain of severe dys- phagia. This condition should be aggressively treated with systemic ketoconazole, fluconazole, or itraconazole. Once the esophageal Candida has cleared, many clinicians choose to leave the patient on fluconazole, 100 mg/ d, to protect not only against the recurrence of esophageal candidiasis but also cryptococcal meningitis. This type of long-term prophylaxis is fraught with the danger that patients may develop resistant Candida albicans or the overgrowth of Cundida krusei, which is resistant to fluconazole. In these cases the patients can be treated with systemic itraconazole to which Cundida krusei is sensitive or with systemic amphotericin B until the resistant Candida infection has cleared.

Fortunately, even though prophylaxis with fluconazole has been widespread for the past 5 years, the emergence of resistant Candida has not become a major problem.16 Systemic fungal infections with Cryptococcus neoformans,l1 Histoplasma capsulatum, Coccidioides i m m i t i ~ , 2 ~ Blastomyces d e r m a t i t i d i ~ , ~ ~ and Spor- othrix schenckii5 must all be treated aggressively withsystemic antifungal agents. In all of these instances, lifelong prophylaxis is im- perative to prevent a recrudescence of the fungal infe~ti0n.l~. l7


NEW DISEASES

The intensive study of severely immunocompromised patients not only affords the clinician the opportunity to study infections in a new environment, but also allows for the appearance of diseases not heretofore described.

HIV-infected patients with fewer than 100 CD, cells often develop small, tense pustules surrounded by a collar of erythema that is intensely pruritic. Biopsy shows a heavy eosinophilic infiltrate, particularly around hair follicles. This condition has been called eosinophilic folliculitis and responds to anti-inflammatory agents such as systemic corticosteroids, ultraviolet light, and systemic itraconazole, but not to other systemic azoles such as ketoconazole and fluconazole. This observation suggests that eosinophilic folliculitis may be caused by a fungal infection that is sensitive only to itraconazole or that the itraconazole is working through some mechanism not yet understood to suppress this inflammatory process.

CONCLUSIONS

For most of us our immune systems work so well that we take for granted the protec- tion that it provides against the host of fungal, bacterial, and viral agents that surround us in our everyday lives. Fungi are ubiqui- tous, and fungal pathogens and other opportunistic infections quickly invade a human host whose immune defenses begin to fail. AIDS and other immunodeficiency diseases are helping us to understand the evolutionary process that provided us with the complex immune system that protects us from these pathogens. We have entered the era in which we are capable of developing safe and effec- tive drugs to protect against these mycotic pathogens as the immune system fails. It is hoped that, in the near future, techniques to restore the immune systems of immunocompromised individuals will be realized.

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University of California Medical Center, San Francisco 350 Parnassus Avenue, Suite 808

San Francisco, CA 94117

fungal infections in immunocompromised individuals

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