Histoplasmosis - Thorax · Histoplasmosis superficial ooze on the left and a small decreasing...

Thorax (1972), 27, 6.

HistoplasmosisA review, and account of three patients diagnosed in Great BritainW. M. MACLEOD, I. G. MURRAY', JEAN DAVIDSON,

and D. D. GIBBS2

Southampton University Western (Chest) Hospital, Oakley Road, Southampton

Active histoplasmosis is rarely diagnosed in Great Britain. We present the illness records of threepatients with disseminated histoplasmosis. In two patients the infection was discovered at necropsyand resulted in caseous destruction of the adrenal glands, and in one of these there was also fungalinvasion of the liver and wall of the aorta. The third patient had Addison's disease and also achronic tongue ulcer from which the fungus was cultured by biopsy.The eight other patients with disseminated histoplasmosis and the six with active localized

disease previously reported in Great Britain are reviewed.The natural history of the disease, with emphasis on the prolonged incubation period of up to

18 years, is described. Granulomatous ulceration of the oropharynx and larynx and caseousdestruction of the adrenal glands may be characteristic features.

Diagnosis usually requires a history of a stay in endemic regions. It is suggested by the clinicalpicture and positive complement fixation or precipitin tests and it is confirmed by culture of thefungus which may also be recognized in histological preparations. Histoplasmin skin tests areusually negative.

Standard treatment is with intravenous amphotericin B, but in our surviving patient a chronictongue ulcer of nine years' duration showed considerable healing after 10 months' oral treatmentwith trirmethoprim-sulphamethoxazole in combination.

Histoplasmosis was first recognized and named asa separate disease by Dr. Samuel Darling whileinvestigating leishmania infections in the CanalZone of Panama (Darling, 1906, 1908). Althoughthe Americas still show the highest incidence of thedisease, infected patients have been found in theFar East, Africa, and the Mediterranean regions.In Europe, the disease is still rare and in GreatBritain infection by the fungus Histoplasmacapsulatum is almost unknown. Less rarely, thedisease, following infection abroad, is first recog-nized in this country at necropsy. We record thehistories of two such patients and of a third patientin whom active disseminated histoplasmosis wasdiagnosed in England during life.

CASE REPORTS

CASE I P.S. was a regular army officer born on23 January 1921. He had served abroad in Europe,Burma, Java, and Malaya. In 1955 he was invalided

lDr. I. G. Murray dicd on 26 July, 19712Present address: Good Hope General Hospital, Sutton Coldfield,Warwickshire

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home with presumed pulmonary tuberculosis. Hischest radiograph showed mottling with some calcifica-tion, but no cavitation, in the right upper lobe.Sputum was negative on microscopy and on culturefor Mycobacterium tuberculosis. After four months'treatment with streptomycin and isoniazid, resectionof the right upper lobe was performed. Direct smearfrom the operative specimen showed scanty acid-fastbacilli but cultures were negative.

In March 1961, during a febrile illness, the chestradiograph again showed mottling in the right upperlung (Fig. 1). Treatment with streptomycin and iso-niazid was resumed. In July he developed anorexia,loss of weight, and skin pigmentation. His bloodpressure was 80/60 mmHg. The liver and spleenwere palpable. Plasma sodium was 122 mEq/l andurine 17-ketosteroids 2-2 mg/day. The Thorn test waspositive. A diagnosis of Addison's disease was madeand he was treated with cortisone, 75 mg daily.

It was at this time that he first noticed a painfululcer on the left side of the tongue. Biopsy of theulcer showed chronic inflammatory granulation tissuewith numerous giant cells but no caseation. Acid-fastbacilli were not seen but the appearances were thoughtto be compatible with active tuberculosis.

In January 1965 he was first admitted to Southamp-ton Chest Hospital. His main complaint was still that

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Histoplasmosis

FIG. 2. Case 1. 1965. Superior view of tongue showingulceration on dorsum and deformity of left margin.

FIG. 1. Case 1. 1961. Tomogram, 5 cm posterior cut,showing pleural 'cap' overlying mottling in right upperlung.

FIG. 3. Case 1. 1965. Postero-anterior chestradiograph showing opacity at apex of righthemithorax with apparent cavitation ? apicalempyema.

of tongue ulceration which had slowly progressedover four years. The tongue showed irregular granu-lomatous ulceration from the left side round underthe tip to the right. There was separate ulceration inthe centre of the dorsum (Fig. 2). He had no coughor sputum. There were no other abnormal clinicalfindings. His peripheral blood picture, electrolytes,serum proteins, and liver function tests were allnormal. The erythrocyte sedimentation rate was 28mm in the first hour (Westergren). The chest radio-graph showed a dense opacity with elongated trans-radiancy filling the apex of the right hemithorax,suggestive of an apical empyema. The remainder ofthe lung fields was clear (Fig. 3).

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The tuberculin skin sensitivity test was positive(Mantoux 1/1,000: 2 cm induration). Histoplasminskin test was negative. Histoplasmin complementfixation test was positive with titres between 1/50 and1 /100. A repeat tongue biopsy showed large numbersof giant-cell histiocytic granulomata (Fig. 4). Therewas no caseation. Definite histoplasma were seenwithin the giant cells. In 'Gridley' preparations the

FIG. 5. Case 1. 1968. Anterior view of tongue showinggranuloma at frenumn and ulceration at left side and on

dorsuln.

yeasts were also seen outside the giant cells andbudding forms were recognized. Re-examination ofthe previous biopsy using Grocott-Gomori hexaminesilver stain demonstrated histoplasma. The organismswere sparse but the apparent budding forms wereunusually conspicuous. Culture of the second biopsygrew Histoplasma capsulatum. The fungus was re-sistant to 500 Ag/ml amphotericin but sensitive to1.000 ,g/ml. It was resistant to 50 ug/ml sulfadoxine(Fanasil, Ro 4-4393) but sensitive to 100 ,ug/ml.

Since the patient refused intravenous therapy withamphotericin, he was treated successively with sul-fadoxine for 11 months, oral amphotericin for 9months, and sulphadimidine for 7 months withintervals between each course. There was slight tem-porary improvement while taking sulfadoxine for thefirst three months but afterwards slow progression ofthe disease in the tongue continued. The wholetongue became scarred and deformed and protrusionwas difficult (Fig. 5). Eating was painful and dis-tressing. The lung lesion had shown no change forat least five years. On the suggestion of one of us(I.G.M.) treatment was started with trimethoprim,160 mg, combined with sulphamethoxazole, 800 mg(Bactrim or Septrin) twice daily. Some healing wasevident at the end of the first month and after 10months this was almost complete except for a slight

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superficial ooze on the left and a small decreasingbutton of granulation tissue under the frenum. Thetongue remains scarred and deformed but is moremobile and free from pain (slight relapse in November1971).CASE 2 G.C., a male railway employee, was born ofBritish parentage in India in 1905. He had lived inCalcutta and travelled extensively in Eastern India.He recalled no illness of significance. In 1947 he cameto stay in England for good and obtained work in acar factory.

In April 1957 he was admitted to hospital with amyocardial infarction complicated by pericarditis andtransient disturbances of rhythm. He recovered andduring the following five years suffered from anginaof effort. He was readmitted in December 1964 withan increase in chest pain. He mentioned that for sixmonths he had slowly lost weight and had poorappetite and ill-defined epigastric and back pains. Hehad noticed increasing fatigue and more recently hadbeen vomiting. He looked ill and wasted. There weresmall areas of vitiligo on the skin of the forearms,but pigmentation was not prominent and was absentfrom the buccal mucosa. An electrocardiogramshowed left bundle-branch block. Serum aspartateaminotransferase was 116 i.u. Plasma electrolyteswere within the normal range. His condition de-teriorated and after two weeks, during which theserum sodium fell to 126 mEq/l, he collapsed anddied.At necropsy the oral cavity, the larynx, trachea, and

main bronchi were normal. The lungs were oedematousand there were a few calcified foci in the left upperlobe. The heart was small-230 g. There was extensivescarring which involved the ventricular septum and theanterior wall of the left ventricle, but there was nogross evidence of recent infarction. The liver and spleenappeared congested.The adrenal glands were symmetrically enlarged,

each measuring 7x5 cm and weighing 65 g. Theirexternal surfaces were smooth and lobulated and thecut surfaces showed complete destruction of bothglands by soft, white caseous material. From themacroscopic appearances tuberculosis was stronglysuspected but no acid-fast bacilli were found in thesmears from the adrenal glands nor in the histo-logical sections; and culture for Myco. tuberculosisproved negative. Routine sections showed replacementof the glands by caseous debris; this was walled offby fibrous tissue containing some non-specific inflam-matory cells. A few multinucleated giant cells werepresent but there was no typical 'tuberculide' reaction.Routine sections also showed numerous tiny ovoidbodies, about 3 A in diameter. These were unstainedbut their somewhat refractile nature made them standout against the necrotic background. They also provedto be doubly refractile and stained positively withPAS and methenamine silver. A diagnosis of adrenalhistoplasmosis was made. Hyphate forms grew inculture and the identity of H. capsulatum was con-firmed by Professor W. St. C. Symmers. There was

no evidence of histoplasmosis elsewhere in the body.

CASE 3 A.S. was a regular soldier born in 1905. Hehad served abroad in Europe, Nigeria, Iraq, theSudan, and India. He developed rheumatoid arthritisin 1948 and returned to England for the last time in1949. He continued work as a commerical travellerfor 10 years until his arthritis forced his retirementin 1959.He was treated at first with a variety of drugs

including phenylbutazone. Corticosteroids werestarted in 1953; for a few months he had ACTHand then cortisone, 75 mg daily, which was continuedup to 1967.

In July 1967, still suffering from progressive rheu-matoid disease, he was admitted to hospital com-plaining especially of lack of energy, lethargy, andundue loss of weight during the previous six months.He had developed a cough with mucoid sputum andwas now short of breath on moderate activity. He hadhad rigors with fever and sweating. On admission thetemperature was 102° F. There were signs of rheuma-toid deformity in both hands and of effusion intothe right knee joint. There were subcutaneous nodulesover both elbows. His spleen was enlarged and theliver edge was palpable and firm. B.P. was 120/80mmHg.

INVESTIGATIONS Haemoglobin 9.9 g/100 ml, serumiron 20 Ag! 100 ml, leucocytes 5,000/mm3, normaldifferential count. Erythrocyte sedimentation rate 53mm in one hour (Westergren). Plasma electrolytesnormal. Plasma albumen 2-1 g/100 ml, globulin 4-6g/ 100 ml. Rose-Waaler D.A.T. positive 64 units.Sputum culture was negative for Myco. tuberculosisbut showed a heavy growth of monilia. In the chestradiograph there was shadowing at the right apex.On the left there were linear densities stretching upand out from the hilar region to the apex. Tomo-graphy confirmed these findings and revealed on theright a thin-walled cavity at the apex, 2x 1 cm. On theleft there were several small transradiancies in alinear 'fibrotic' network in the upper lobe (Fig. 6). Theappearances were suggestive of tuberculous diseasewith probable activity at the right apex.

Treatment was started with streptomycin, sodiumPAS, and isoniazid. An attempt to wean him fromcorticosteroids failed and they were continued asprednisone, 5 mg twice daily. Progress was unsatis-factory with continuing fever and loss of weight. Theliver increased in size. Serum bilirubin rose to 16 mg/100 ml, serum aspartate aminotransferase to 46 units/ml, and alkaline phosphatase to 30 units/ml. Liverbiopsy showed granulomatous lesions scatteredthroughout the parenchyma; many of these lesionswere surrounded by a mantle of polymorphs, whichwere also present in the portal tracts. Haemoglobinwas 10-2 g/ 100 ml and leucocytes 2,400/cmm3, with88% neutrophils and 12%' lymphocytes. Platelets werereduced to 49,000/mm3. A marrow aspiration samplewas essentially normal with slight plasma-cell in-filtration.

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W. M. Macleod, 1. G. Murray, Jean Davidson, and D. D. Gibbs

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FIG. 6. Case 3. 1967. Tomogram section of both upper lungs, 10 cm posterior cut,showing a thin-walled cavity, 2 x 1 cm, at right apex and linear network in leftiopper lobe.

His condition deteriorated further. He developed aleft-sided spontaneous pneumothorax and died a fewdays later in December 1967.At necropsy the body was emaciated. The larynx

and trachea were normal but the bronchi containedfrothy sputum. The right lung showed an apicalcavity and the surfaces of the lungs were studdedwith giant emphysematous bullae. The heart was ofnormal size but the left ventricle was hypertrophiedand the right coronary artery partly occluded byatheroma. The abdominal aorta was atheromatouswith a very thickened but soft wall. The liver weighed3.025 g but, apart from some pallor, appeared normal.The spleen weighed 122 g and showed one white areabut no other significant abnormality. The right kidneywas of normal size and the left was enlarged; in boththere were several caseous areas. Both adrenalsshowed multiple areas of caseation.

Histologically, in both adrenals and kidneys therewere foci of necrosis containing numerous ovoid re-fractile bodies about 3 ,u in diameter. There were alsonumerous organisms in the surrounding macrophages.The organisms could be demonstrated by Grocott'smethod, and their capsules stained by periodic acidSchiff technique (Fig. 7). Morphologically the ap-pearances were compatible with H. capsulatum. Theorganisms could also be demonstrated in the athero-matous wall of the aorta (Fig. 8). Scanty organisms

were present in the small granulomata in the liver.The lungs showed areas of necrosis surrounded byfibrous tissue. No organisms could be demonstrated,and the appearances were more suggestive of arheumatoid aetiology than of a previous histoplasmainfection.

DISCUSSION

The first patient in Britain to be recognized withactive histoplasmosis was a soldier who hadserved abroad in India and the Sudan as well asin Europe (Derry, Card, and Wilson, 1942). Theoccurrence of infection in persons who have neverleft these islands is extremely rare. There are twopossible instances. Limerick (1951) briefly reportedfinding the fungus in pus from an appendicularabscess. The fungus was not cultured andSymmers (1956a) has questioned the reliabilityof the diagnosis. Symmers himself culturedhistoplasma from a lymph node removed forbiopsy from a man of 56 years. The patienthad always lived in England or Ireland. In 1936he cut his forehead in Ireland. He developed scarsarcoid in 1950 and in the following year showedevidence of disseminated sarcoidosis. This resolved

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FIG. 7. Case 3. Section from adrenal gland showing numerous histoplasma organisms in matrix. Grocott's method, x 550

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TABLE ISUMMARY OF PATl NTS WITH ACTIVE DISSEMINATED HISTOPLASMOSIS DIAGNOSED IN GREAT BRITAIN

Histo- Comple-Refer- Sex Agel Work Countries Home Clinical Features Dura- Biopsy Culture plasmin mentence Period" tion3 Histoplasma Present Skin Fixation

Test Test

Derry M 30 General India, India Cough, pleurisy, fever, 9 mth A.M. Cervical and +ve 0 0et a!. labourer Sudan, 3-4 yr, loss ofweight. Cervical inguinal nodes(1942) France Sudan lymph nodes +, and Died

Armed 2-3 yr, abscess, liver+, P.M. Rectroperiton-services France spleen + eal mass (adrenals

4 mth not identified);tonsils, cervicalnodes, spleen,peritoneum, smalland large bowel

Locket M 32 Armed Near East, 6-7 yr Abdominalpain, fever, 12-15 P.M. Liver, spleen, +ve ve 0et al. services North Africa, loss ofweight, mouth mth lymph nodes, lung,(1953) India ulceration, anaemia, bone marrow,

spleen +, liver+, lung Died thyroid, adrenals,shadows, skin ulcers and skin

Poles and M 45 Armed France, 6 yr Sore throat, hoarse 9 mth A.M. Larynx -ve -ve 0Lavertine services Nigeria, voice, miliary shadows(1954) Burma chest radiograph, Died P.M. Larynx,

Post office fever, loss ofweight, trachea, lungs, andclerk cough, dyspnoea, adrenals

diarrhoea, spleen+Earle M 62 Forestry India, Few Loss ofweight, 10 mth A.M. Tongue, anus 0 0 Anti-et al. Pakistan mth anorexia. tiredness, comple-(1960) mental change, tongue Died P.M. Adrenals, mentary

ulcer, anal ulcer, fever, kidneysanaemia, spleen +,liver+, haematuria

Miller M 61 Yardman Dardanelles 40-41 Cough, sputum, 6 mth P.M. Lungs, hilar 0 0 0et al. cotton yr breathlessness, loss of lymph nodes,(1961) mill weight, extensive Died adrenals, prostate

bilateral shadowingchest radiograph

Murray F 66 Housewife India 10 yr Reticulosarcoma under A.M. Bone marrow + ve ve 0and treated with cortico- ? 12 mthSladden steroids; fever, P.M. Heart, lungs,(1965) anaemia, purpura, Died liver, spleen, and

oedema, spleen+ +, other organs Idrowsy, albuminuria 2

Partridge F 42 Housewife Malaya, ? 1 yr Dental abscess, fever, 3 yr Larynx, subphrenic + ve ve +veand India, lethargy, dyspnoea, plus abscess 1/512Tanser Ceylon, loss of weight,(1966) U.S.A., dysphagia, liver+, Alive

Hawaii, spleen+, laryngealJapan, ulcer, adrenal failureHong Kong

Aldridge M 63 ? Burma ? 17 yr Loose bowels, loss of 5 yr A.M. Colon, spleen, -4-ve 0 Precipi-et al. weight, lassitude, granulation tissue tation(1970) liver +, spleen +, Died yve

anaemia, ankle P.M. Adrenals, Yeast-oedema; laparotomy; gastric ulcer abscess phasecolon perforation; wall, also in small I comple-large retroperitoneal vessels ofpancreas, mentmass; secondary liver, lungs, and fixationhaemorrhage, gastric kidneys +ve 1/10artery

Present M 40 Armed Burma, 6yr ? pulmonary tubercu- 9 yr Tongue ve -ve veseries (1) services Malaya, losis; tongue ulcer, 1/160

Java, loss ofweight, AliveEurope Addison's disease,

spleen +(2) |M 58 Railway India 16 yr Loss of weight, 2 wk P.M. Adrenal glands -4-ve 0 0

employee anorexia, weakness,vomiting, epigastric Diedpain, myocardial

_________________________________________________________ |infarction

(3) M 63 Armed India, 18 yr Rheumatoid disease |12mth P.M. Adrenal glands, 0 0 0services Iraq treated with cortisone; kidney, liver, aorta

Sudan, lethargy, recurrent DiedNigeria, fever, bilateral upperEurope lobe shadowing chest

radiograph, anaemia.spleen +, liver -

' Age at onset of symptoms.I Period between return from abroad and onset of symptoms.3Duration of illness from first symptom.

0 no information.A.M.= antemortem; P.M. -postmortem.



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TABLE IISUMMARY OF PATIENTS WITH LOCALIZED ACTIVE HISTOPLASMOSIS DIAGNOSED IN GREAT BRITAIN

Histo- Comple-Reference Sex Age Work Countries Clinical Features Biopsy Culture plasmin ment

Skin FixationTest Test

Duncan M 63 ? West Africa Papulocircinate lesions on skin; biopsy +ve +ve 0 0(1945;1947)Limerick M 35 ? Never Inguinal abscess following appendicectomy Pus -ve 0 0(1951) +ve

Hutchison M 72 Mining India, After 14 yr in Great Britain developed husky +ve -ve 0 0(1952) engineer Malaya voice; ulceration ofright vocal cord; biopsy;

healed in 3 yr

Symmers M 56 ? Never 1936 cut forehead; 1950 scar sarcoid; 1951 lung +ve +ve +ve 0(1956a) infiltration, generalized peripheral lymph node

enlargement; biopsy-sarcoidosis, resolutionin 12 mth; 1955 recurrent supraclavicularlymph node enlargement; biopsy

Symmers M 28 Student Nigeria 1951 pustule on cheek, ? insect bite; healed with +ve +ve -ve 0(1956b) nodule, 1953 nodule ulcerated; biopsy

Symmers F 23 Student Nigeria Annular skin lesion over lower sternum slowly +ve +ve +ve 0(1956b) enlarging over 2 yr; biopsy

spontaneously during the next 12 months. In 1955two small cervical nodes re-enlarged and it wasfrom one of these that the fungus was cultured.Another possible instance of infection occurring

in these islands was in a man aged 61 years. He wasa yardman in a cotton mill. At his work he hadclose dusty contact with bales of cotton fromAmerica and Nigeria. Forty years previously hehad spent a year in the Dardanelles but otherwisehad always lived in England. He died from ex-tensive disseminated disease thought to betuberculous until the fungus was seen in necropsyspecimens (Miller, Ramsden, and Geake, 1961).

If the fungus is present in these islands, why isthe initial infection so rare? Two small skin testsurveys have shown no positive reactors(McCracken, 1948; Evans, 1949). Knight, con-sidering this problem, has pointed out that themean summer temperature compares favourablywith areas in Canada from which histoplasmainfection has been reported and also with Bergenin Norway where skin test surveys have yielded4-7% of positive reactors (Knight, 1968). Knightsuggests that a further survey in Great Britain,especially in those areas with an adequate rainfalland high acid soil, might be rewarding.

Altogether, there have been eight reports ofactive disseminated histoplasmosis first diagnosedin Great Britain (Table I). To these we now addthree further examples. There have also beenreports of patients with apparently localized histo-plasmosis (Table II). In three of these there was a

skin lesion, in one the larynx was involved, in onea cervical lymph node was infected, and in a sixth

an appendix abscess, as cited above. There havebeen several reports of healed pulmonary diseasepresenting with multiple calcified foci and thediagnosis presumed from the history of travelabroad and a positive skin test reaction (Arblaster,1950; Crofton, 1950; Sakula, 1953; Leigh andThomas, 1955).

THE CLINICAL PICTURE

The natural history of the disease is outlined inTable III. Infection most commonly occurs fol-lowing the inhalation of soil dust laden with fungalspores, the primary lesion developing in the lungs.There may be a single focus or several, or evenmultiple bilateral foci. When the latter heal withcalcification they present a distinctive radiographicpicture (Arblaster, 1950; Crofton, 1950). Primary

TABLE III

Primary lesion1. Lungs-single, several or multiple bilateral foci with related

adenitis; heals with calcification2. Skin (? oropharynx)

Post-primary lesions1. Lungs

(a) Acute bronchopneumonia(b) Chronic infiltration, fibrosis, cavitation, and round foci.

Very similar to tuberculosis. Fungus rarely found in sputum.

2. Disseminated disease(a) Acute, see text(b) Chronic, see text

3. Other thoracic presentations(a) Pleurisy with effusion(b) Mediastinitis; superior vena-caval obstruction(c) Pericarditis, acute or constrictive

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lesions of the skin are less common. Three patientspresenting with solitary skin granulomas have beenrecognized in Great Britain (Duncan, 1947;Symmers, 1956a, b) (Table II). In all three casesinfection started in West Africa. Local skingranulomata may be a feature of the Africandisease with Histoplasma duboisii infection (Lucas,1968). While disseminated skin lesions are commonto both types, primary skin foci in Americanhistoplasmosis-H. capsulatum infection-are saidto be extremely uncommon (Furcolow, 1960).Primary gastrointestinal infection, though experi-mentally demonstrated, has not been proven inman. Children may present with gut infection,often with related lymphadenitis, but this followsprimary lung disease or is part of disseminatedhistoplasmosis (Soper, Silber, and Holcomb, 1970).The primary lung focus usually heals without

producing symptoms. The diagnosis is reasonablyinferred from a positive skin reaction to histo-plasmin and a negative response to tuberculin, andpossibly a calcified scar in the chest radiograph.In a few persons the lung disease develops eitheras an acute bronchopneumonia or more indolentlywith infiltration, cavitation, and fibrosis indistin-guishable in the radiograph from pulmonary tuber-culosis. The fungus is rarely found in the sputumand the diagnosis may again depend on differentialskin sensitivities. The patient whose illness wasrecorded by Miller et al. (1961) presented withacute bronchopneumonia and died with dis-seminated disease. In our first case, histoplasmosiswas not considered at the time of lobar resection;also while cultures were negative for Myco. tuber-culosis, acid-fast bacilli were seen in the smearsfrom the right upper lobe. In our case 3 nohistoplasma were seen in the lungs at necropsyand no cultures were taken. It is possible that inboth these patients there was a coincident tuber-culous infection though in the third case the histo-logical appearances suggested rheumatoid lungdisease. Pleurisy with effusion is an infrequentdevelopment (Schub, Spivey, and Baird, 1966).In some persons histoplasma infection presents asa 'round' pulmonary focus simulating a tuber-culoma or a nodular growth.

Dissemination of the fungus to other parts ofthe body may or may not be accompanied byrecognizable lung lesions. It is this form of diseasewhich is the outstanding presentation of activehistoplasmosis in Great Britain. The disseminationmay be acute and fulminating, mimicking acutehaematogenous tuberculosis with fever, loss ofweight, enlarged liver, and palpable spleen. Theremay be generalized lymphadenopathy, meningitis,

and miliary dissemination in the lungs, deathfollowing in a few months from the onset of infec-tion (Table I).

Chronic disseminated histoplasmosis is muchmore insidious and prolonged in its invasion (case1). It may remain hidden and unrecognized untilthe sudden development of terminal adrenal failure(cases 2 and 3). Many years of apparent goodhealth may follow infection abroad before deathin this country (Table I).The disease may affect many parts of the body

but there are two characteristic lesions which areoften in the picture:

1. Granulomatous ulceration in the oro-pharynx,tongue, tonsils, pharynx or larynx: whilelocalized orolaryngeal lesions may rarely occur ontheir own (the case reported by Hutchison in 1952in this country is a possible example), they areusually features of generalized disease (case 1). Inthe diagnosis of these granulomata confusion withtuberculosis is the main difficulty, but the absenceof pulmonary disease with tubercle bacilli in thesputum almost excludes a tuberculous aetiology.Sarcoidosis can affect the nasal mucosa but is un-likely to present with an oral granuloma. Blasto-mycosis and coccidioidomycosis should be con-sidered in patients coming from endemic areas inthe American continents. Darling originally found,while surveying the Panama zone, that histoplas-mosis was confused with leishmaniasis. This caneasily be distinguished by appropriate staining.Malignant ulcers with macroscopic mimicry areeasily identified histologically (Bennett, 1967).

2. Adrenal gland involvement, with almost totalcaseous destruction but often little clinical or bio-chemical evidence of such destruction until neardeath: the destroyed glands are packed withparasites.The selection of the adrenal glands as a favour-

able site for the growth of the histoplasma fungushas been recognized for many years (Parsons andZarafonetis, 1945). Baker (1968) comments thatthe organisms grow well in the steroids of theadrenal cortex. Crispell, Parson, Hamlin, andHollifield (1956) report on four patients in whomthe diagnosis of histoplasmosis and Addison'sdisease was established before death. They col-lected 36 other case reports from the literatureand comment that antemortem recognition is rela-tively rare. In the 11 patients found in GreatBritain with disseminated histoplasmosis theadrenal glands were definitely diseased in nine,and in the remaining two the glands were auto-lysed or not identified separately. In three of thenine patients adrenal destruction was not sus-

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pected during life. In three others adrenal failurewas considered but could not be established dur-ing life. In the seventh patient the diagnosis wasmade only 24 hours before death, and only in theremaining two patients was Addison's disease con-firmed and treated successfully with survival.

In England tuberculosis is still a frequent causeof Addison's disease. Out of 56 persons betweenthe ages of 25 and 69 years who died from thisdisease in London during the years 1960-64, 28died from tuberculosis of the adrenals, 27 hadsimple atrophy of the glands, and one person hadhistoplasma infection (Mason, Meade, Lee, andMorris, 1968). Though the latter infection is stillrare in this country, histological confusion withtuberculosis is easy unless appropriate search ismade for both fungi and bacilli.

In our third patient the abdominal aorta wasatheromatous with a thickened but soft wall.Histoplasma organisms were seen in this atheroma-tous area (Fig. 8). The invasion of the aorta bythe fungus is one of the rarer events in dis-seminated histoplasmosis. Rosenbaum, Schweppe,and Rabin (1964) record the necropsy findings ina patient who died from rupture of a thoracicaortic aneurysm into the left lower lobe. In addi-tion, there was evidence of constrictive pericarditisand a spontaneous pneumopericardium followinga bronchopericardial fistula. H. capsulatum wasdemonstrated in the diseased area. Welsh, Coppola,and Capelli (1969) described the case of a 47-year-old man who developed an aneurysm of thefemoral artery. He had an enlarged liver andspleen. On biopsy granulomatous lesions werefound in liver and muscle. He then developedtongue ulceration, ruptured his abdominal aorta,and showed signs of meningoencephalitis. Biopsyof the aortic wall showed evidence of histoplas-mosis. The aorta was repaired with a Dacrongraft and following treatment with amphotericinhe made an excellent recovery.

Histoplasmosis can also involve the cardio-vascular system either as progressive mediastinitiswith superior venacaval obstruction (Hewlett,Steer, and Thomas, 1966), or as pericarditis, acute(Kaplan and Sherwood, 1963), or chronic and con-strictive (Klieger and Fisher, 1962).Disseminated histoplasmosis certainly occurs in

the American continents, but it would seem prob-able that those recognized with this disease inGreat Britain were infected in India or the FarEast (Table I). There is no particular occupationhazard except where individuals such as agricul-tural workers, demolition labourers, and caveexplorers are exposed to the dust from bird

droppings. The patient whose illness is recorded byMiller et al. (1961) died from acute disseminateddisease. At his work he had been exposed to dustsfrom cotton bales imported from America andNigeria, but no proof of infection from this sourcewas obtained.

THE DIAGNOSIS

The diagnosis in Great Britain should always beconsidered in anyone showing the features of dis-seminated disease in whom there is no proof oftuberculous infection and who has lived in endemicareas during the previous 20 years. Confirmationof possible histoplasma infection may readily beobtained by serological methods such as comple-ment fixation or precipitin tests. These are positivein a high percentage of active infections, particu-larly if the disease is disseminated. Skin sensitivitytests using the antigenic histoplasmin to demon-strate a delayed 'tuberculin' type of sensitivity havebeen of great value in studying the epidemiologyof histoplasmosis. They are of little use and maybe misleading in the diagnosis of disseminateddisease for in Great Britain and elsewhere theyare usually negative with this form of infection.Absolute confirmation can only be obtained duringlife by culture of biopsy material. On conventionallaboratory media at temperatures around 260 Cthe organism grows as a typical filamentoustungus. On certain selective media at 370 C thefungus adopts a yeast-like morphology. In vitrothe yeasts are oval, approximately 15-20 X 3 54, and usually bud at the poles in actively growingcultures.

Histologically the appearances are not specific.There may be a marked giant-cell reaction withoutnecrosis as in our first case (Fig. 4); or necrosismay be prominent with surrounding macrophages.Invasion of the reticuloendothelial system ischaracteristic. In routine haematoxylin and eosinpreparations, the organisms can be seen as slightlyovoid bodies, 1-5 ,u in diameter, with an achromaticdoubly refractile capsule. Their presence may beconfirmed by more specific stains such as theperiodic acid Schiff reaction and by Grocott'smodification of Gomori's method. The latter hasthe advantage of staining dead organisms (Figs 7and 8) (Symmers, 1960).

TREATMENT

The treatment of choice is amphotericin givenintravenously daily for three to four months.

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W. M. Macleod, 1. G. Murray, Jean Davidson, and D. D. Gibbs

Sulphonamides have been used successfully inSouth America, and Negroni (1964) reportedencouragingly on the value of sulfadoxine whichwas used in the initial treatment of our first patient.There are no available reports on the use oftrimethoprim-sulphamethoxazole in the treatmentof histoplasmosis. The encouraging response to itsuse in our first patient suggests that this form ofsulphonamide combination is worth further trial.

In addition to specific antifungal agents, sup-portive measures may be required; in particular,corticosteroids to counter adrenocortical insuffi-ciency. Though cortisone on its own was used formany years in two of our patients, such cortico-steroid therapy without amphotericin cover mayhave serious consequences (Utz, 1968; Murray andSladden, 1965).

We wish to thank Dr. John Graham for the culturereports and sensitivity results of the organism fromcase 1. We are grateful to Dr. A. W. Spence forpermission to publish details of case 2 and to Dr.Leslie McGee of Barking Hospital, Essex for thenecropsy findings. We are also indebted to Dr. JohnDadds of St. Mary's Hospital, Portsmouth for theclinical details of case 3, and to Dr. R. D. Clay andDr. M. A. Rashid for the necropsy reports.

Sulfadoxine (Fanasil-Ro 4-4393) used in the initialtreatment of case 1 was kindly supplied by RocheProducts Limited through the courtesy of Dr. I.Lennox Smith.We are indebted to the Wessex Regional Hospital

Board for a contribution towards the cost of colourreproduction.

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