Disseminated Candida tropicalis in a patient with chronic mucocutaneous candidiasis.

Abstract: Chronic mucocutaneous candidiasis is a heterogeneous group of immunodeficiencies associated with persistent candidal infections. Patients with chronic mucocutaneous candidiasis are rarely associated with systemic infections caused by other fungi, but almost never by Candida. The authors report a case of a 16-year-old with chronic mucocutaneous candidiasis who developed a fungemia with Candida tropicalis.

Key Words: Candida, chronic mucocutaneous candidiasis, disseminated

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Chronic mucocutaneous candidiasis (CMC) is a heterogeneous group of immunodeficiencies in cell-mediated immunity toward organisms of the genus Candida. A suggested classification of CMC includes four syndromes: autosomal recessive CMC (early onset), diffuse CMC, CMC with endocrinopathy, and late onset CMC (with associated thymoma). (1) Patients with CMC have persistent or recurrent Candida infections of the oropharynx, skin, and nail apparatus. The infections are usually due to C albicans, and often become refractory to standard therapy.

Despite the abnormal cellular immune response to Candida, patients with CMC rarely develop disseminated fungal infections. There have been three patients reported in the literature with candidal meningitis in CMC. (2,3,4) There is a single report of disseminated infections with other fungi such as Cryptococcus neoformans and Histoplasma capsulatum. (5) We report a 16-year-old patient with CMC who developed Candida tropicalis fungemia. The only other recorded case of a disseminated Candida infection in CMC was in the father of our patient. (6) The reported patient, her father, and affected sister, all may have a unique familial variant of CMC that predisposes to deep candidal infections, and may lead to new perspectives on a poorly understood disease.

Case Report

A 16-year-old white female with CMC and common variable immunodeficiency, treated with biweekly intravenous immunoglobulin, presented with a one-week history of progressive dyspnea on exertion. Relevant past medical history included numerous episodes of oral, esophageal, and vaginal candidiasis previously controlled with intermittent courses of amphotericin B and imidazoles. Previous infectious complications included Epstein-Barr virus-associated chronic active hepatitis treated with azathioprine and corticosteroids, disseminated Bartonella henselae, and granulomatous Pneumocystis carinii pneumonia. Most recently, candidal esophagitis recalcitrant to fluconazole and amphotericin B had been successfully suppressed with caspofungin, 0.7 mg/kg once weekly.

At admission the patient was afebrile and denied cough or mucous production. Her oxygen requirement had recently increased from a baseline of 2 L per minute (LPM) to 3 LPM via nasal cannula, with her [O.sub.2] saturation decreasing from between 94 and 97% to approximately 80% on walking. Physical examination at admission revealed decreased breath sounds over the right lung field with no rhonchi or rales. She appeared chronically ill and smaller than stated age, but had an otherwise unremarkable examination. Pertinent laboratory findings included the following: white blood cell count 47,000/m[m.sup.3], with a manual differential of 62 neutrophils, 4 bands, 19 lymphocytes, 14 monocytes; normal liver function tests with bilirubin 0.5 mg/dL, prothrombin time 14.2 seconds; and a hemoglobin of 5.2 g/dL. A chest radiograph revealed a new nodular density in the left upper lobe. Lymphocyte proliferation testing showed a normal response to phytohemagglutinin and concanavalin A, but minimal response to tetanus toxoid.

The patient was continued on caspofungin and increased to daily dosing (0.7 mg/kg/d) for a possible fungal pneumonia. She later underwent a splenectomy for management of chronic thrombocytopenia and mucosal bleeding, but subsequently required two rounds of sclerotherapy for management of three grade II esophageal varices secondary to portal hypertension. She received multiple transfusions of blood products for numerous episodes of hematemesis and severe anemia. Bronchoscopy revealed an ulceration in her distal trachea.

She developed conjugated hyperbilirubinemia (peak 36.5 mg/dL). The bilirubin decreased after the caspofungin was discontinued. She had fever to 40[degrees]C despite therapy with trimethoprim-sulfamethoxazole, meropenem, and vancomycin. All blood and urine catheter cultures were negative at this time. The patient was started on amphotericin B lipid complex (5 mg/kg/d) as well as ciprofloxacin for continued presumptive fungal infection. Transfer to the pediatric intensive care unit was required for worsening respiratory distress. Renal function declined and the patient was switched from amphotericin B lipid complex to liposomal amphotericin B at the same dose. Candida tropicalis was isolated from two separate peripheral blood cultures on days consistent with a worsening clinical picture. No antifungal susceptibilities were performed on the C tropicalis isolate. After continued liposomal amphotericin B she had several subsequent negative blood cultures. She later developed uncontrollable gastrointestinal tract bleeding, despite octreotide infusion and numerous transfusions, and died.

Discussion

Systemic fungal infections have rarely been reported as a complication of chronic mucocutaneous candidiasis. (3,5) In a review of CMC cases complicated by invasive fungal infections, Kauffman et al (5) reported 6 cases, 4 of which were complicated by Histoplasma capsulatum meningitis, one with Cryptococcus neoformans, and one with Candida albicans meningitis. There are only four other cases of systemic candidal disease in CMC patients (Table 1). One of them was the father of our patient. (5,6)

The lack of systemic fungal infections in the setting of CMC has been partially explained by deficits in T-cell responses limited to Candida infection. Protection from mucocutaneous disease is thought to be mediated primarily by adaptive immune responses (ie, cell-mediated immunity), while innate immunity protects against systemic infections. (7) Some patients with CMC have a documented defect in T-cell responses to Candida and a normal phagocytic activity, although these defects are not universally observed. (8) In addition, generalized and Candida-specific antibody responses are normal in CMC patients. (7,9) Our patient had normal lymphocyte proliferative responses to pokeweed mitogen, phytohemagglutinin, and concanavalin A, while having weak responses to both Candida antigens and tetanus toxoid. Between the ages of 4 and 8 years, she developed progressive panhypogammaglobulinemia. She also lacked antibody production to diphtheria and tetanus toxoids, and required replacement therapy with intravenous immunoglobulin since age 8 years. She had normal percentages of B-lymphocytes until age 8 years, and they were absent after 9 years of age. More subtle humoral immune defects have been described in patients with CMC who also experienced recurrent bacterial infections with encapsulated organisms. (10,11) Having laboratory findings consistent with common variable immunodeficiency is likely to have contributed to the pulmonary insufficiency, but does not explain the fungemia found in our patient, since chronic and systemic fungal infections are not common features of this immunodeficiency. (7)

Initially it was felt that our patient's positive blood culture might be due to contamination; since the blood cultures were obtained by peripheral venipuncture, there was the possibility of simple contamination with the chronically skin-colonizing Candida species. However, two previous mouth cultures, one previous vaginal culture, and numerous stool cultures all revealed only C albicans, whereas our two blood cultures yielded C tropicalis. These observations support the concept that CMC is a heterogeneous group of diseases, with defects that all lead to the decreased cell-mediated response in vivo to Candida species.

Again, it is worthwhile to note that the father of this patient had a similar disease course, including an instance of candidal septicemia. Systemic candidal infection in this family may be the result of an uncharacterized defect predisposing them to systemic fungal infections. This patient also experienced severe and unusual manifestations of infections not typically encountered in patients with CMC. These included Epstein-Barr virus-associated chronic active hepatitis, hepatic bacillary angiomatosis due to Bartonella henselae, and granulomatous Pneumocystis carinii pneumonia. Her clinical course suggests that she had a more profound in vivo T-lymphocyte defect. Her B-lymphocyte deficiency may have been a consequence of treatment with immunosuppressive agents, or defective T- and B-cell interactions.

Conclusion

This report, coupled with the earlier reports, should alert the clinician to be aware of the possibility of systemic fungal infection and rare opportunistic infections, as well as the conventional mucocutaneous disease in patients with CMC.

Table. Case report summary of CMC patients with disseminated candidal
infections (a)

                    Age/     CMC        Causative     Involved
Reference           Sex (a)  onset (b)  organism      area(s)

Kaufmann et al [5]  27/M     12         C albicans    meninges, brain
Germain et al [2]   28/F     16         C albicans    meninges
Germain et al [2]   27/M     NR         C albicans    meninges, brain,
                                                        kidney, mycotic
                                                        aortic ancurysm
Maggiore et al [3]   8/F      1         C albicans    meninges,
                                                        disseminated,
                                                        blood
Current report      16/F     Birth      C tropicalis  disseminated,
                                                        blood

                                      Candidal  Affected
                                      antigen   family
Reference           PHA (c)  PWM (d)  response  members

Kaufmann et al [5]  normal   NR (c)   negative  NR
Germain et al [2]   normal   NR       negative  2 sisters
Germain et al [2]   normal   NR       negative  1 brother
Maggiore et al [3]  reduced  NR       negative  NR
Current report      normal   normal   low       Father and sister

(a) Age reported in years, "M" denotes male, "F" denotes female.
(b) Age in years of CMC onset.
(c) Phytohemagglutinin response.
(d) Pokeweed mitogen response.
(e) "NR" denotes a result that was not reported.

Accepted December 8, 2003.

References

1. Fitzpatrick TB, Johnson RA, Wolff K. Color atlas and synopsis of clinical dermatology, common and serious diseases. New York, McGraw-Hill, 2001, ed 4, pp 720-721.

2. Germain M, Gourdcau M, Herbert J. Case report: familial chronic mucocutaneous candidiasis complicated by deep candidal infection. Am J Med Sci 1994;307:282-283.

3. Maggiore G, Marseglia G, Duse M. Septicemia and meningitis as a complication of liver biopsy in a girl with chronic mucocutaneous candidiasis [letter]. J Ped Gastroenterol Nutr 1982;1:614.

4. Quie PG, Chilgren RA. Acute disseminated and chronic mucocutaneous candidiasis. Sem Hematol 1971;8:227-242.

5. Kaufmann CA, Shea MJ, Frame PT. Invasive fungal infections in patients with chronic mucocutaneous candidiasis. Arch Intern Med 1981;141:1076-1078.

6. Imperato PJ, Buckley CE, Callaway JL. Candida granuloma: a clinical and immunological study. Arch Dermatol 1968;97:139-146.

7. Lilic D, Gravenor I. Immunology of chronic mucocutaneous candidiasis. J Clin Pathol 2001;54:81-83.

8. Djawari D, Simon M Jr, Burkhart B. Macrophage functions in patients suffering from chronic mucocutaneous candidiasis. Arch Dermatol Res 1983;275:412-414.

9. De Moraes-Vasconcelos D, Orii NM, Romano CC, et al. Characterization of the cellular immune function of patients with chronic mucocutaneous candidiasis. Clin Exp Immunol 2001;123:247-253.

10. Bentur L, Nisbet-Brown E, Levison H, Roifman CM. Lung disease associated with IgG subclass deficiency in chronic mucocutaneous candidiasis. J Pediatrics 1991;118:82-86.

11. Herrod HG. Chronic mucocutaneous candidiasis in childhood and complications of non-Candida infection: a report of the pediatric immunodeficiency collaborative study group. J Pediatrics 1990;116:377-382.

RELATED ARTICLE: Key Points

* Chronic mucocutaneous candidiasis is rarely associated with systemic candidal infections.

* The patient's father had had chronic mucocutaneous candidiasis, and also died as a result of a systemic candidal infection, raising the possibility of a variant familial form of chronic mucocutaneous candidiasis that predisposes to systemic candidal infections.

* The systemic infection in this case was caused by Candida tropicalis, a rare cause of fungemia in children.

Terry C. Dixon, MD, PHD, William J. Steinbach, MD, Daniel K. Benjamin Jr, MD, MPH, PHD, Larry W. Williams, MD, and Laurie A. Myers, MD

From the Department of Pediatrics, the Division of Pediatric Infectious Diseases, the Division of Pediatric Allergy and Immunology, and the Mycology Research Unit, Duke University, Durham, NC.

Dr. Benjamin received support from the National Institute of Child Health and Human Development (R03HD42940-01).

Reprint requests to Terry C. Dixon, MD, PhD, DUMC 3127, Department of Pediatrics, Duke Children's Hospital and Health Center, Duke University Medical Center, Durham, NC 27710. E-mail: [e-mail]