Oral medicine

Oral thrush, or acute pseudomembranous candidiasis

A clinicopathologic study of forty-four cases

Thomas Lehner, MB., B.S., F.D.X.K.C.S., B.D.S., London, England

DEPARTMENT OF DEX’TAL MEDICINE, GVY’S HOSPITAL

T he increased number of reports of disseminated candidiasis has brought about renewed interest. in oral thrush. The rising incidence is thought to be associated with iatrogenic factors ; antibiotics, corticosteroids, and cytotoxic drugs have been shown to promote candidiasis.g The mouth is often the only site involved, but it may serve as an early and readily accessible indication of disseminated candidiasis. Although the clinical manifestations of thrush as seen in infants and debilitated patients are well recognized, there is little in- formation about the natural history and pathologic process of candidiasis.

The purpose of this article is to describe the natural course of oral thrush as observed in a series of elderly, debilitated patients. The different pathologic reactions will be described, and an attempt will be made to relate these to the clinical features of candidiasis. Therapeutic factors which promote the disease will be considered, and the treatment and prophylaxis will be discussed.

CLINICAL ANALYSIS

In the present. series forty-four ward patients with oral thrush were exam- ined. I inspected the mouths of thirty-four of these patients twice daily during the course of the disease. The remaining ten patients were seen at postmortem examination, and the clinical details were made available. In a male medical ward during the months of December, January, and February eighteen out of a total of I88 patients (9.6 per cent), developed thrush, but of the thirty-six patients who died of other diseases twclvc had thrush. Thus, 33 per rent of the patients who died manifested oral thrush.

The ages varied between 34 and 84 years, the mean being 64. IIowcrer,

27

28 Lshner

Table I. Systemic diseases in forty-four patients \vitll ceandidiasis

Sumbw of pticnts -__

14

9 8 4 3 2 2 2

Systtmic tlist 0s~

Respiratory fai luw, hronc~hopncl~nloni:~ rlue to ~*hroni~ hrowhitis or astllrma

C’cmbrovascular accident C‘arcGnomatosis Uremia (:oronary thrombosis Acute leukemia Hodgkin’s disease Peritonit,is

no children were examined. Thrrc were thirty-fire men and nine women, but this ratio is biased in favor of males because of the larger proportion of male pa- tients under care. All the patients suffered from severe systemic disease; as shown in Table I, and thirty died. Thrush preceded death by 3 to 35 days, and seventeen (or 57 per cent) died within 10 days after the appearance 0:’ thrush.

CLINICAL FEATURES

There were few oral symptoms at,tributable to thrush, but ten patients complained of sore mouth or throat, and six spoke of “furring” of the mouth. In three patients the pain was sufficiently severe to r&rict fluid intake, causing severe dehydration. The lesions of thrush were first seen as soft white or gray “ papules, ’ ’ 2 to 3 mm. diameter, surrounded by slight erythema. Some lesions remained discrete, while others coalesced within 1 to 2 days (at times even within 8 hours), to give rise to a soft, white, raised plaque or membrane (Figs. 1. and 2). The lesions could be rubbed off, leaving a reddened mucosa. Twenty- eight patients had white or gray papules or flakes with surrounding erythema on the buccal mucosa. Thirteen of them had smooth erythematous tongues, eleven had a gray membrane covering part or all of the t,ongne, seven had a similar involvement of the palate (mostly the soft palate), and in two patients each the lips, gum, floor of the mouth, and oropharpnx lvere affected. In seven other patients the dorsum of the tongue was covered by a gray, raised, furry membrane (Fig. 3), with no signs of thrush in the rest of the mouth. Six pa- tients had a gray membrane which covered the entire mucosal surface of the mouth except the palate. Finally, three patients displayed a fiery red, dry, and atrophic mucosa of the mouth and oropharynx. Twenty-one out of thirty-four patients had a yeasty odor in their mouths, which was quite characteristic; yeast h~ulitosis is thought to be an appropriate term for this. Twenty-three of the thirty-four patients were denture wearers, and none had evidence of “den- ture sore mouth. ”

Thrush often disappeared spontaneously. Indeed, in twelve patients lesions cleared and re-formed repeatedly, coinciding clearl,v with improvement or dc- terioration, respectively, of t,ho patient’s general clinical st,ate. In only three patients had thrush developed at a time when the general condition was im- proved.

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Oral thrush 29

E ‘ig. 1. Thrush of the soft palate showing coalescence of the individual lwions.

E ‘I$. .z?. Hyperplastic, hemorrhagic gingiva in acute leukemia, showing acute ps men11 nanous candidiasis of the interdental papillae.

wdo-

E lhedding of the plaques in eight patients gave rise to a painful erythi ema- tous and atrophic mucosa. In two patients, on admission t,o hospital, the oral and pharyngeal mucosa was severely painful, fiery red, atrophic, and dry . BY then the patients had received a variety of antibiotics, without any clil nical imp1 sovement. Oral swabs grew Candida albicans and, on questioning of the medj ical practitioners responsible for the former treatment, it became evi dent

that t,he patients had previously had florid thrush. Tt sums that thrush in itself is seldom painful, but when the plaques are shctl the denuded erythema- tous mucosa may give rise to sevcrc sj-mptoms.

Angular cheilitis was conspicuousI?- absent in all cases. It was, indeed, of some interest to see how abruptly the lesions stoppctl at, thr mucocutaneous junction.

THE EFFECT OF DRUGS

The administration of antibiotics, corticosteroids, and rytotoxic agents was recorded, as these may enhance candidiasis. Twenty-nine patients (66 per cent) received one or more antibiotics prior to the appearance of thrush. Corti- costeroids were used in thirteen patients, and all but two of these were also receiving antibiotic therapy. Two patients developed thrush after sucking Corlan tablets (hydrocortisone sodium succinate) for 6 to 10 days. Cytotoxic drugs were used in three patients, two received Gmercaptopurine, and one was given nitrogen mustard. These patients were also receiving corticosteroids OI

antibiotics. One patient was a diabetic. 1 t is evident that, in most patients many fact,ors known to promote thrush were present.

SPREAD

Though there was no reason to suspect, on clinical grounds, spread of candi- diasis beyond the mouth and oropharynx, five of ten patients on whom post-

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Oral thrush 31

mortem examination was performed were found to have candidiasis of the pharynx, larynx, or esophagus. Furthermore, one patient had disseminated candidiasis involving the heart, kidneys, adrenals, tongue, thyroid, and lungs.

INVESTIGATION

Bacteriologic examination was carried out in all but five cases. C. a&cans was found in twenty-three cases, as shown by chlamydospore formation in corn meal agar. In eleven cases a yeastlike organism was found, but the species was not further identified. In the remaining five cases, no yeasts were grown. The hemoglobin, white blood count, and other investigations reflected the major underlying disease and, therefore, did not throw any light on the candidiasis. The only significant feature was the presence of neutropenia in three pa- tients.

TREATMENT

Nystatin was administered to twenty-six patients; sixteen were given one tablet (100,000 units), which was to be kept in the mouth, four times daily. In thirteen patients the lesions disappeared clinically within 1 to 3 days. Five patients were given four nystatin tablets daily to swallow (500,000 units per tablet) ; this resulted in clearance of the lesions in two patients within 4 days. Tn four patients nystatin suspension was applied to the oral mucosa four times daily, but in only one patient did the lesions clear in 5 days. Vitamin B complex was given to nine patients, in six by intramuscular injections, without apparent result. Indeed, episodes of thrush actually set in during vitamin B therapy.

HISTOPATHOLOGY

In seventeen cases specimens were obtained from the tongue, cheek, or pharynx within 5 minutes to 36 hours after death. Stains used for the fungus included Gram, periodic acid-Schiff, Gridley, and Grocott. The fungus is some- times clearly shown by means of hematoxylin and eosin stain, but often the organism may be difficult to see and occasionally the fungus will not be found without the aid of special stains. With hematoxylin and eosin the yeast cells appear as faintly basophilic oval bodies, 2 to 6 microns in size. The pseudo- hyphae are faintly basophilic, septate structures, 2 to 4 microns wide, showing branching and budding of yeast cells. The cytoplasm is not homogeneous ; clear oval areas can be seen in the yeast cells and along the pseudohyphae, and these arc useful features in differentiating the fungus. Periodic acid-Schiff stains the fungus red and the cell membrane deep red, and Grocott’s method stains it black ; both these stains were particularly useful in demonstrating Candida (Fig. 4). Gram stain was helpful in showing bacteria in relation to Candida, while Gridley’s method was less effective than periodic acid-Schiff or Grocott’s stain. Candida occasionally may be confused histologically with Aspergillus; the dis- tinguishing features are the sporing head and radiating and branching filaments which show little protoplasmic detail. Artifacts (for example, stringing of nuclei) are sometimes confused with Candida, and fibrin is a common source of error. These can be excluded by careful examination of the morphologic

features and the use of phosphotungstic acid-hcmatos~lin, which stains fibrin deep blue.

The pseudomembrane seen in t,hrush usually shows necrotic tissue, with desquamated epithelium, keratin, parakeratin or fibrin, and food debris, mutinous material, leukocytes, and bacteria. All this is matted together anti anchored down to the epithelium by the fungal hyphae (Fig. 5).

Yeast cells are usually found in company with pseudohyphae, and it is exceptional to find one form exclusively. Most commonly, yeast cells are located superficially and pseudohyphae deeply in the keratin layer or in the superficial third of the prickle-cell layer. Invasion seems to take place by the proliferating pseudohypha.e, which are strikingly orientated at right angles to the surface. The fungus is not found in the corium except in necrosis or ulceration of the mucosa, which is best seen in patients with leukemia.

The reaction of the mucous membrane to the fungus varies, although there may be no tissue response. With regard to the epithelium, there may be intra- cellular edema in the prickle cells (Fig. 5). This may lead to rupture of the cells, forming spaces in t,he stratum spinosum ; this weakens the epithelium and facilitates separation of layers of prickle cells. Leukocytes may be found scattered diffusely in the epithelium, and polymorphonuclear and mononuclear

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Oral thrush 33

Fig. 6. Fig. 7.

Fig. 6. Section of tongue showing pseudohyphae in heaped-up keratin, with underlying edema and leukocytic infiltration. Yeast cells are also seen superficially between the keratin masses. (Periodic acid-Schiff stain. Magnification, x130; reduced y&)

Fig. 7. Edema and microabscesses in the prickle-cell layer of same tissue as shown in Fig. 6. (Hematoxylin and eosin st,ain. Magnification, x130; reduced 4;;.)

Fig. 8. Shedding of the plaque of pseudomembranous candidiasis, carrying with it layers of prickle cells. (Hematoxylin and eosin stain. Magnification, x120; reduced ye.)

34 LPh7l(Jr O.S.. 0.M.B 0.f’. .I u1.v. IN4

leukocyt,es ma)- be aggregated in the fluid-filled spactss, forming Irlic.l~oal)scc~ssts (Figs. 6 and 7). Occasionally the coritun shows a sprinkling of I(ukocytcs, but, with necrosis there is hyperemia and &ma and not uncommonly blood vxsels arc thrombosed and contain the fungus, although this dots not necessarily lead to dissemination.

Healing of acute pseudomembranous candidiasis is associated with shedding of the plaque. This process is helped by intracellular edema and may end the disease without further symptoms. In some cases, honcrer, the plaque may bc shed, carrying with it several layers of prickle cells (Fig. 8). The cpithelium then becomes red, atrophic, and sort. This process (acntc atrophic canditliasis)

Fig. 9. Acute atrophic candidiasis showing a fern lroken hyphac iu the superficial parts of the prickle-cell layer. (Grocott’s stain. Maguifiwtion, x230 ; wcluwtl I,& )

Fig. 10. Section of tongue from a patient with disseminated candidiasis, showing a grau- uloma with C. albicnns centrally and leukocytes peripherally. (Periodic, ari+Schiff stain. Magnification, x120; reduced I/u.)

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Oral thrush 35

may be the result of more severe intraepithelial edema and microabscesses. Histologically, acute atrophic candidiasis shows atrophic epithelium with a few broken hyphae in the superficial parts of the stratum spinosum (Fig. 9). Hyper- sensitivity may be an additional factor in the development of the acutely in- flamed mucosa, as shown by Conant and associates2

In disseminated candidiasis the tongue musculature may also bc involved, producing a granulomatous reaction as shown in Fig. 10.

DISCUSSION

Epidemiology

The epidemiology of adult candidiasis is not clear. In the debilitated patient, infection may be endogenous from the gastrointestinal tract or exogenous as a result of contact with carriers, contaminated objects, or patients with candidi- asis. Lepper and colleagues7 have shown that Candida may spread from one patient to another in hospital wards, and this may well have been the case in the present series. By contrast, thrush in infants is due to exogenous infection by direct contact with vaginal candidiasis during parturition, and drugs play no part in its pathogenesis.ll

Clinical features

Frequent inspection of the mouth in elderly debilitated patients has shown that oral thrush is fairly common. The incidence of 9.6 per cent found in this series compares with 15 per cent recorded by Boggs and associates’ in patients with terminal malignant disease. Thrush develops in a high proportion of pa- tients shortly before death, and there is a close correlation between the presence of candidiasis and the general state of the patient. It was striking to see the appearance or disappearance of thrush following deterioration or improvement of the patient’s condition. Deterioration was associated with lethargy, when the patient did not eat or drink, so that the plaque remained undisturbed. When the patient improved and returned to activity, the plaque of thrush was shed. While Roth and co-workers lo have demonstrated a deficiency of anti-candidal substance in the sera of patients with leukemia, lymphoma, myeloma, poly- cythemia, and aplastic anemia, they were unable to show a similar deficiency in patients with carcinomatosis.

In the present series, the role of antibiotics, corticosteroids, and cytotoxic drugs as promoting agents in the development of candidiasis is confirmed.

BACTERIOLOGY

The isolation of C. albicans from the mouth is of no diagnostic signjficance, for the organism may be found in about 34 per cent of normal mouths, as shown by Lilienthal.8 However, a direct smear may assist in differentiating the sapro- phyte which is found in the yeast phase from the pathogen found in the mycelial phase. This has been shown convincingly in fecal smears of enteric candidiasis by Kozinn and Taschdjian,4 in oral thrush in infants by Taschdjian and Kozinn,12 in. skin candidiasis by Whittle and associates,1” and in experimental candidiasis by Gresham and Burns.” That the mycelial phase is the invasive

CL%, o.lu. & 0.1’. .I ulv, 1964

form is confirmed by the appearance of sections of c3ndidal lesions n-here the constant pattern seen in twrnt,v (~;IS(JS is ttic presence of’ ytinst, cells superficially and proliferating pseudohyphac~ tl~p in the tissnc i Figs. 4, 3,. atI(l 6 I .* Morc- over, twenty smears have been c~saminrti from patients without signs 01’ candi- diasis but in whom (‘andida was cultured from the saliva, and none of thcsct demon&rated the mycelial phase.

Treatment and prophylaxis

Nystatin has been shown to be useful in the treatment of candidiasis. Any failures in the present series were probably due to inadequate concentration of nystatin at the site of the lesion. Nystatin is poorly absorbed from t,he gastro- intestinal tract, so that a. continuous high local concentration is achieved only by keeping the tablets in the mouth and not swallowing thern. Xystatin suspension does not att,ain this aim, as it is quickly washed away, and its use should be confined to infants or adult patients with cxcessivcly painful mouths. Bniline dyes are useful, but they are messy and often cannot be applied effectively. No complications have followed the oral administration of nystatin, even in a patient taking 500,000 units daily for 9 months.

Prophylactic administration of nystatin is recommended for severely debili- tated patients, particularly those receiving antibiotics, corticosteroids, and cyto- toxic drugs. Optimum results arc achieved by holding a tablet of nystatin (500,- 000 units) in the rnouth four times dail)-. In this way, a persistent high concen- tration of the drug is achieved in the most yulnerablc sites-the mouth, the pharynx, and the esophagus. Oral surgical procedures especially extractions, should not be carried out in t,hc presence of thrush. It is important that nystatin be given until the clinical lesion is cleared and the fungus can no longer be cultured.

Classification

In 1962 I proposed a classification of candidiasis in which the disease is divided into acute and chronic varieties. Acute pseudomembranous candidiasis is the most common form and, as has been shown, may lead to the acute atrophic variety. Medical advice may be sought by the patient in the latter stage because of the pain, a.nd the diagnosis may be missed unless the condition is borne in rnind and a careful history, oral examination (especially such shielded sites as the sulcus in the tuberosity and retromolar region, t,o find remaining patches of thrush), and bacteriologic study are carried out. Chronic hyperplastic candidiasis is an important consideration in a differential diagnosis.” The nails, mouth, face, or scalp are characterist,ically involved, and there may be hypo- parathyroidism and adrenal deficiency. The white plaque cannot be removed, it is resistant to the common methods of treatment, and the histopathology is specific. Leukoplakia should not bc> confused with chronic hyperplastic candidiasis. Lichen planus and white spongy nerus have many features which distinguish them from candidiasis.

*In a control group of thirty postmortem cases without eandidiasis the cheek mucosa was examined histologically and showed no fungal hyphae.

01-d thrush 37

SUMMARY

1. Clinical features are presented in forty-four cases of oral thrush with special reference to the natural course of the disease. Thrush may disappear spontaneously, and the onset of pain often may be related to shedding of the plaque.

2. Oral thrush was found in about 10 per cent of severely debilitated patients, and it affected about one third of all dying patients in this series.

3. The mouth may be the source or an early site of infection in widespread candidiasis.

4. Histopathologic changes are described in fourteen cases, and the mech- anism of shedding of the plaque is believed to be important in the healing of acute pseudomembranous candidiasis, as well as the pathogenesis of acute atrophic candidiasis.

I wish to thank Professor M. A. Rushton and Dr. R. A. Cawson for their helpful advice

and criticism in the preparation of t,his paper. I am indebted to Professor C. V. Harrison

for his kind permission to study the postmortem material at the Postgraduate Medical School, London, and to Dr. 0. Garrod for permission to investigate the patients under his care at

the Barnet General Hospital. Moreover, I am grateful to Mr. J. E. Hutchinson for the

photomicrographs and to Mr. B. A. Jones and Mr. \V. Brackenlmry for the clinical photo-

graphs.

REFERENCES

1. Boggs, D. R:, Kearns, J. J., Williams, A. F., and Howell, A., Jr.: Thrush in Maliguant Neoplastic. Dmease,.A. M. A. Arch. Int. Med. 107: 354, 1961.

2. Conant, N. F., Snuth, D. T., Baker, R. D:, Callaway, 6. L., and Martin, D. S.: Manual of Clinica. Mycology, ed. 2, Philadelphia, 1954, W. B. Saunders Company.

3. Gresham, G. H., and Burns, M.: Tissue Invasion by Candida: Progress in the Biological Sciences in Relation to Dermatology, London, 174-183.

1960, Cambridge University Press, pp.

4. Kozinn, P. J., and Taschdjian, C. L.: Enteric Candidiasis; Diagnosis and Clinical Con. siderations, Pediatrics 30: 71-85, 1962.

5. Lehner, T.: Oral Pathology in the pp. 75-8%. ;“c”h”.

Child, International Academy of Oral Pathology,

6. Lehner, ronic Candidiasis! Brit. D. J. (In press.) 7. Lepper, M. H., Lockwood, J., Spies, H. W., and Rubenis, M.: Studies on the Epidemiology

of Strains of Candida in Hospital Wards, Antibiotic Ann., p. 666, 1958.1959. 8. Lilienthal, B.: Studies of the Flora of the Mouth, Australian J. Exper. Biol. & M. SC.

28: 279-286, 1950. 9. Louria, D. B., Stiff, D. P., and Bennett, B.: Disseminated Moniliasis in the Adult, Medicine

41: 307-337, 1962. 10. Roth, F. J., Jr., Martin, J., and Goldstein, M. I.: Inhibition of Growth of Pathogenic

Yeasts by Human Skin, J. Invest. Dermat. 36: 383, 1961. 11. Shrand, H.: Thrush in the Newborn, Brit. M. J. 5266: 1530, 1961. 12. Taschdjian, C. L., and Kozinn, P. J.: Laboratory and Clinical Studies of Candid&is

in the Newborn Infant, J. Pediat. 50: 426,. 1957. 13. Whittle, C. H., Moffatt, J. L., and Davis, R. A.: Paronychia or Perionychia: Aetio-

logical Aspects, Brit. J. Dermat. 71: l-11, 1959.