open lung biopsy in children with diffuse lung disease

Archives of Disease in Childhood, 1974, 49, 27.

Open lung biopsy in children with diffuse lung diseaseC. J. HEWITT,* D. HULL, and JEAN W. KEELING

From The Hospitalfor Sick Children, Great Ormond Street, London

Hewitt, C. J., Hull, D., and Keeling, J. W. (1974). Archives of Disease inChildhood, 49, 27. Open lung biopsy in children with diffuse lung disease.Open lung biopsy is occasionally the only way to diagnose certain diffuse lungdisorders in childhood. The clinical histories of 24 children with diffuse lung diseaseand the histological appearance of material obtained at open lung biopsy are reported,and published reports are reviewed.

Open lung biopsy is rarely performed in children.From the few published reports it was generallythought to help in establishing, confirming, orexcluding a diagnosis in children with obscurediffuse lung disease (Weng et al., 1968; Stringer etal., 1968; Toyama et al., 1971). During 13 years,from 1959 to 1972, 24 children with diffuse lungdisease have undergone open lung biopsy at thishospital. This paper reports the clinical andhistological features in these cases and discusses theindications and value of open biopsy.

Materials and methodsAll children in the series had severe progressive lung

disease. Radiologically the pathological processappeared diffuse, and its nature could not be determinedby any other means. Included in the differentialdiagnosis ofeach case was at least one treatable condition.Lung biopsy was obtained from the lingula in 20 cases,

but in 4 the lingula appeared normal and the biopsy wastaken from an area which appeared to be most severelyaffected radiologically.The lung biopsy was taken unfixed to the histology

department. In those cases where Pnewnocystis cariniipneumonia was suspected, impressions were made fromthe cut surfaces ofthe lung on glass slides and stained byGeimsa's method, and in some cases the biopsy wasdivided and a small part frozen. The remainder of thebiopsy was fixed in buffered formalin before paraffinembedding. Paraffin-embedded sections were stainedwith haematoxylin and eosin, Van Geison's method,Weigert's elastic tissue stain, Fordon and Sweet's methodfor reticulin, Geimsa and Grocott's modification ofGomori's methenamine silver stain, and Perls's stain foriron. Frozen sections were stained with haematoxylinand eosin and Jones's method.

Received 3 July 1973.*Present address: Addenbrooke's Hospital, Cambridge.

ResultsThe clinical details and histological results of all

the biopsies are in Table I.In 5 cases, the paraffin-embedded sections of the

biopsy showed typical changes of P. cariniipneumonia. In one of these cases the changes werepresent in haematoxylin and eosin stained cryostatsections, enabling diagnosis to be made on the sameday as biopsy. In no case did we find that a positivediagnosis could be made from smears or impressionpreparations. Three biopsies from children withcombined immune deficiency showed patchythickening of alveolar walls with polymophonuclearleucocyte infiltration and no evidence of P. cariniiinfection.

Biopsies from 2 infants contained considerableamounts of haemosiderin in macrophages and septain addition to fibrosis. 8 biopsies showed thechanges of diffuse fibrosing alveolitis as the term isused by Scadding and Hinson (1967). Changesranged from histiocytic infiltration of the alveolarwalls with widespread desquamation ofmacrophagesinto the alveoli, with bizarre giant cell forms andperipherally sited lymphoid follicles, to gross fibrosisof alveolar walls with obliteration of many alveoli.Some biopsies showed a mixture of the abovefindings. The changes ofCase 8 are described morefully. The biopsy from one girl contained multiplegranulomata consisting of polymorphonuclearleucocytes and histiocytes with normal lung betweenthem. This child was later shown to have chronicgranulomatous disease.The complications of the procedures were few.

3 patients had small pleural effusions afterthoracotomy, which resolved spontaneously, and 3had subcutaneous surgical emphysema. In only

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TAB]Clinical details andfindings in

Case no. Age at onset of illness Presenting features Chest x-ray appearances

Anorexia, upper respiratory symptoms;chest infection at 19 mth

Weak suck, poor weight gain; recurrentcoryza, cough, intermittent fevers fromage 8 mth

Cough, tachypnoea, fever

Episodes of cough, dyspnoea, cyanosis,fever, bronchospasm

Episodes of cough, wheezing, anorexia,lethargy

Poor weight gain, intermittent cough;dyspnoea at age 3k yr

Tachypnoea, slow feeder; cyanosed at age5 mth

Slow feeder; poor weight gain; cough,wheeze, general malaise at 2 mth

Slow feeder, coryza, and persistent coughat 2 mth

Tachypnoea and clubbing of fingers at 9mth of age

Persistent vomiting, failure to thrive,cough

Anorexia, cough, fever dypsnoea

Poor weight gain; vomiting, diarrhoea,cough

Chest infection, cyanosis, cough

Cough, fever, dyspnoea, vomiting

Cough, slow feeder

Septic spot on leg; at 2 mth tachypnoeaand rib retraction, diarrhoea

Recurrent episodes of 'bronchitis',anorexia, poor weight gain

Weak cry, abnormal chest movements,tachypnoea

Feeding difficulty and vomiting; at 6mth episode of dyspnoea and cyanosis

Ulcerated nodular lesion on leg; laterepisodes of cough, dyspnoea, heartfailure

Slow feeder; episodes of cyanosis whencrying; cardiac failure

Vomited cow's milk; recurrent episodesof cough, fever, tachypnoea

Tachypnoea, failure to thrive,hepatomegaly

Diffuse linear and patchy shadowing,mainly perihilar

Diffuse mottled shadowing

Diffuse patchy consolidation and linearshadowing; loss of cardiac outline

Overinflated chest; diffuse linearshadowing; cardiomegaly andprominent pulmonary artery

Diffuse linear and mottled shadowingmainly perihilar

Diffuse mottled shadowing obscuringdiaphragm and heart borders

Minimal changes; suggestion of decreasetranslucency all areas

Diffuse hazy shadowing of varyingdensity and loss of cardiac outline

Diffuse opacity most marked in perihila:region

Minimal mottled shadowing both lungs

Diffuse hazy shadowing, mainly perihilasome nodularity in perihilar region

Diffuse consolidation sparing periphery

Diffuse hazy shadowing with some lineapatchy shadowing right middle lobeand left upper lobe

Diffuse patchy opacities

Diffuse hazy shadowing with air-bronchogram

Consolidation of right lower lobe, patch:shadowing left base

Patchy changes both upper lobes L > Flungs overinflated; changes of rapidonset

Diffuse nodular patchy shadowing,particularly perihilar

Diffuse hazy shadowing, high diaphragn

Diffuse changes with linear shadows andpatchy opacities, mainly perihilar;consolidation at right base

Extensive patchy shadowing bilaterally

Extensive patchy shadowing

Diffuse mottling and linear shadows

Diffuse bilateral mottling, mainlyperihilar; normal heart size

one was there a serious complication: this was a largepneumothorax that required reinsertion of a pleuraldrain, after which it resolved. Only one child diedwithin 24 hours of the lung biopsy, and his deathwas not related to any complication of the open lung

biopsy procedure. He was already in extremis

before biopsy. 3 other children died within oneweek of the lung biopsy, but again death wasattributable to the underlying lung problem ratherthan to a complication of the biopsy itself.At the time of writing, 13 of the 24 patients have

died. Of those with cryptogenic fibrosing alveolitis,

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Open lung biopsy in children with diffuse lung disease

Idren who had open lung biopsy

Age at biopsy Histological diagnosis Final clinical diagnosis Outcome

Cryptogenic fibrosing alveolitis








No histological abnormality


P. carinii pneumonia





Nonspecific inflammatory changes





Noncaseating granulomata

Nonspecific inflammatory changes,some haemorrhages

Pulmonary haemosiderosis andfibrosis

Pulmonary haemosiderosis andfibrosis

Fibrosing alveolitis and features ofautoimmune disease

Fibrosing alveolitis



Fibrosing alveolitis; evidence ofautoimmune disease




Probable fibrosing alveolitis

Probable fibrosing alveolitis

Combined immune deficiency stateand pneumocystis pneumonia

Hypo-y-globulinaemia andpneumocystis pneumonia

Combined immune deficiency state

Hypo-y-globulinaemia

Resolving pneumocystispneumonia and bacterialpneumonia

Combined immune deficiency stateand bacterial pneumonia

Combined immune deficiencystate; disaccharide intolerance

Multisystem disease with evidenceof autoimmune state

Bilateral diaphragmatic palsy ofunknown aetiology; pneumonia

Methylmalonic acidaemia,possibly viral pneumonia andpulmonary haemorrhage,cirrhosis, mental retardation

Chronic granulomatous disease

Ventricular septal defect,persistent ductus arteriosus;large left to right shunt

Probable idiopathic pulmonaryhaemosiderosis with irondeficiency anaemia

Infradiaphragmatic totalanomalous pulmonary venousdrainage

Died age 6j yr

Alive, improving; aged ilk yr

Well; aged 9 yr

Died aged 5 yr 7 mth

Well; aged 12i yr

Died aged 4k yr

Died aged 11 mth

Alive, tachypnoeic; aged 3k yr

Alive; fairly well; aged 9 mth

Alive, aged 6tyr

Died aged 9 mth

Alive (not seen since aged 4 yrin 1961)

Died aged 10 mth

Alive (not seen since aged 6 yr in1969)

Died aged 1 yr 2 mth, 1 weekafter biopsy

Died at 6 mth, 1 week aftebiopsy

Died 24 hr after biopsy

Died aged 3 yr 1 mth

Died 12 dy after biopsy

Died age 7 yr 4 mth

Alive, well, aged 8i yr

Well, aged 4* yr

Improving, aged 3* yr

Died 4 dy after biopsy

4 have died. In the pneumocystis pneumoniagroup 3 died, these being the 2 with combinedimmune deficiency state and one who was apparentlyimmunologically normal. The 2 survivors both hadhypo-y-globulinaemia. Of the nondiagnostic and'normal' biopsy group, 4 died.

The following case reports illustrate the mainclinical groups.

Case reportsCombined immune deficiency state and P.

carinii pneumonia. Case 13. A male horn 2 weeks

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Hewitt, Hull, and Keeling.~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~ __r_EF_:% i~~~~~~~~~~~~ p *Aw 6. . 11

FIG. 1.-Case 13. P. carinii pneumonia. Alveoli arefilled byfoamy material; there is thickening and cellular infiltrationof the alveolar walls. (Haematoxylin eosin. x 133.)

postmature, after a normal pregnancy, by normaldelivery and weighed 3-4 kg. At 10 weeks of age hefailed to gain weight, and began to vomit and to havediarrhoea. On admission to hospital he was found tohave oral thrush, a nasal discharge, and conjunctivitis.Investigation suggested a combined immune deficiencystate.When he was transferred here at 5 months of age, both

his length and weight were below the 3rd centile. Smalllymph nodes were palpable in his neck and inguinalregions but no tonsils could be seen. There were norespiratory symptoms or abnormal signs. On x-ray thelung fields were clear and no thymic shadow was seen.The lymphocyte count varied from 74 to 336/mm3.

Lymphocyte function tests showed a partial lymphocytetransformation response to phytohaemagglutinin, withexcessive unstimulated activity. Though Candida wasgrown from a mouth swab, the Candida skin test wasnegative. Immunoglobulin levels were IgG 260 mg/100ml, IgA 0%, IgM 78% of reference normal serum. Hisblood group was 0 rhesus positive but the isohaemag-glutinins at 5 months of age were anti-A 1:1, anti-B 0.Faecal fat excretion was 50% of the oral intake and aglucose tolerance test gave a flat curve. Sweat electrolyteconcentrations were normal.

Progress. Human y-globulin was given from the 5thmonth at a dose of 0-1 g/kg body weight. At 6 monthsof age he developed tachypnoea with a cough and chestx-ray showed widespread hazy shadowing. A lungbiopsy was arranged. In view of serious deterioration,he was started on pentamidine 4 mg/kg intramuscularlydaily immediately, 48 hours before biopsy.

Histology report. There was diffuse thickening of thealveolar walls with cellular infiltration, mainly histiocytic,

but lymphocytes and occasional plasma cells werepresent. Many alveoli were filled with foamyeosinophilic material in which basophilic 'dots' were seen(Fig. 1), though in others this material was seen only inpatches lining the alveolar walls. Geimsa stainingshowed clear cysts containing up to 8 strongly basophilicbodies lying within the foamy material. In sectionsstained by Grocott-Gomori's methenamine silvermethod the foamy material is black (Fig. 2).

Occasional macrophages were seen within alveoli. Nopolymorphonuclear leucocytic infiltration was present.No increase in reticulin, collagen, or elastic fibrils couldbe shown in the alveolar walls.Having confirmed the diagnosis of pneumocystis

pneumonia, the pentamidine was continued for onemonth. Clinically and radiologically his respiratoryproblem improved. However, severe diarrhoea withmalnutrition became an increasing problem despite a dietfree of disaccharides and added medium chain tri-glycerides. He became severely emaciated and diedfrom a Staphylococcus aureus septicaemia at 10 months ofage.

At necropsy the abnormal findings were a minutethymus, atrophic lymph nodes throughout the body,absent tonsils. Lungs weighed 62 g and 56 g and werebulky, pink, well aerated, oedematous; no pleuraleffusions, adhesions at thoracotomy site. Histologicalexamination confirmed the absence of lymphoid folliclesin lymph nodes, tonsillar area, spleen, and appendix.The thymus comprised only the supporting frameworkand vasculature.The lungs contained aterectatic foci and there was

compensatory emphysema. Some alveoli containedfragments of foamy eosinophilic material in whichbasophilic dots were seen: many more contained oedema

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Open lung biopsy in children with diffuse lung disease

FIG. 2.-Case 13. P. carinii pneumonia. Some of the alveoli are dilated; the foamy material is closely applied to thealveolar walls. (Grocott-Gomori. x 133.)

fluid. Occasional alveoli contained macrophages withfoamy cytoplasm. Congested blood vessels were presentin alveolar walls but there was no cellular infiltration.Alveolar epithelium was a flattened layer.

Combined immune deficiency syndrome andlung showing 'nonspecific' inflammatory changes.Case 16. A female born at 37 weeks' gestation weighing3 * 5 kg. Her brother died the previous year withcombined immune deficiency. She was well until 4weeks ofage when she developed a cold, became 'snuffly',and sucked poorly. One week later she developeddiarrhoea which led to her admission at 6 weeks of age inFebruary 1969.On examination she looked a healthy baby, with weight

on the 25th centile. No superficial lymph nodes couldbe palpated. She had a distressing cough but clinicallyand on x-ray the lung fields were clear.The lymphocyte count varied between 374 and 574

cells/mm3. Lymphocyte transformation tests wereinitially normal, but later the response to phyto-haemagglutinin was reduced. Skin tests to Candida andto dinitrofluorobenzene after previous exposure werenegative. Serum immunoglobulins on admission wereIgG 440 mg/100 ml, IgA 5% and IgM 20% of thereference normal serum, but these later fell. Noisohaemagglutinins were detected at 4 months of age.No thymic shadow was seen on x-ray.

Progress. Human y-globulin was given: 0 05 glkgdaily for 5 days followed by weekly injections of 0 025g/kg intramuscularly. At 2 months of age she had aninfusion of her father's bone marrow, and this was felt tohave a transient beneficial effect.At 4 months of age she developed a persistent cough

with fever. Rales were heard over the right lower lobe.

Chest x-ray showed consolidation in the right lower lobe,and patchy shadowing at the left base. Broad spectrumantibiotics were given without improvement. Over a3-week period x-rays showed an extensive andprogressing condition, and an open lung biopsy wasperformed from the right upper lobe. Histologicalexamination showed that the bronchi and bronchiolescontained mucopurulent exudate. The alveolar wallswere thickened by histiocytic and polymorphonuclearleucocyte infiltration which was also present in thealveoli. No increase of collagen, reticulin, or elastictissue was seen in the alveolar walls. No foamy materialwith staining characteristics of P. carinii was present. Asmall right apical pneumothorax was noted one weeklater. The presence of pneumocystis, cytomegalicinclusion disease, and fungal infection were excluded.Antibiotics and human y-globulin were continued, buther course continued to be downhill and she died at 6months of age. A blood culture taken on the last day oflife grew Esch. coli. Necropsy revealed a diffusebacterial pneumonia.

Cryptogenic fibrosing alveolitis confirmedhistologically. Case 8. A male born at term bynormal delivery, weighing 3*2 kg, and cried immediately.From birth he was slow to feed and gain weight. At 2months of age he developed a cough accompanied bywheezing and general malaise. At 11 weeks of age hewas admitted to hospital when he was noted to havemoderate dyspnoea and central cyanosis. His chest wasoverinflated and coarse rales and expiratory rhonchicould be heard in all areas. No other abnormal physicalsigns were to be found.Hb was 10- 9 g/100 ml, white blood count 9000/mm3 of

which 39% were polymorphonuclear cells and 53%lymphocytes, with 6% monocytes and 2% eosinophils.

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FIG. 3.-Case 8. Fibrosing alveolitis. Thickening of the alveolar walls and desquamation of alveolar lining cells whichcompletely fill some alveoli, aggregation of lymphocytes on right. (Haematoxylin eosin. x 200.)

Chest x-rays showed patchy shadowing in both lungfields, which became more extensive in the weeks afteradmission. ECG showed some right ventricularhypertrophy. Blood urea, electrolytes, and sweatelectrolytes were normal. Duodenal juice enzymeconcentrations were also normal. Urine examinationshowed an excess oflactose, glucose, and sucrose, and thestools contained excess galactose, glucose, and fructose.Bacteriological investigations included a rubellahaemagglutination inhibition titre of 1: 8 which, whenrepeated at 4 months of age, had fallen to 1: 4. Toxo-plasma dye test was negative. The cytomegaloviruscomplement fixation titre was 1: 4 and remained un-changed, and tests for syphilis were negative. Myco-plasma was not isolated from the throat swab and coldagglutinins were not present. Cine swallow showednormal deglutition and chest screening showed poorrespiratory excursions with some air trapping. Serumimmunoglobulins were IgG 720 mg/100 ml, IgA 16%and IgM 140% of reference normal serum. Plasma andurinary amino acid pattems were normal.Therapy before biopsy included oxygen, antibiotics,

digoxin, physiotherapy, and a disaccharide-free diet.His condition steadily deteriorated and an open lungbiopsy was performed at the age of4 months. Histologyof the lingular sample showed diffuse thickening of thealveolar walls with histiocytic infiltration (Fig. 3).

Increased reticulin was laid down around the histiocytesand collagen fibrils were present. Some alveolicontained macrophages. Bacterial cultures of lungtissues produced no growth. After biopsy he wasstarted on prednisolone 10 mg daily, and thereaftersteady improvement was noted both clinically andradiologically. After 10 days the prednisolone dose wasreduced to 7-5 mg daily and he deteriorated again.Respiratory function tests showed diminished lungcompliance with increased airway resistance andincreased minute volume. His dose ofprednisolone wasincreased to 10 mg daily and once more he improved.The prednisolone was reduced gradually and stoppedafter one month. At this time chest x-ray was normal.He was discharged but was readmitted 3 weeks later withrecurrence of his original symptoms, and again chestx-ray showed extensive patchy shadowing, mainlyperihilar. Steroids were started again, followed byfurther clinical and radiological improvement. Theywere discontinued in September 1970. He remainedwell until May 1972, when chest x-ray showed anincrease in heart size and indistinct heart margins, due tothe extensive, mainly perihilar, shadows in both lungs.He was given a further course of prednisolone.

Probable cryptogenic fibrosing alveolitis;normal lung biopsy. Case 9. The previous

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Open lung biopsy in children with diffuse lung diseasepregnancy of this child's mother had been complicatedby the development of a chorionic carcinoma, for whichshe was successfully treated with methotrexate; thistreatment was completed 6 months before his conception.The pregnancy was complicated by threatened abortionsat 19, 23, and 26 weeks' gestation. Labour was inducedand he was bom at 39 weeks' gestation by breechdelivery. He breathed spontaneously, weighed 3 * 2 kg,and was breast fed satisfactorily, though his weight gainwas poor. He was otherwise well until 2 months of agewhen he developed a persistent cough with occasionalvomiting. Treatment with penicillin had no beneficialeffect and he was admitted to the local hospital at 4months of age, when a provisional diagnosis ofpneumonia was made. Chest x-ray showed a granularinfiltration in both lungs. ECG was normal. Despitetreatment with ampicillin, flucloxacillin, and digoxin hecontinued to deteriorate.

Investigations included Hb 13-1 g/100 ml, whiteblood count 9000/mm3 with neutrophils 50%, lympho-cytes 48%, and monocytes 2%. Platelet count was273,000/mm3 and ESR 37 mm/hr. Sweat sodiumconcentration was 21 and 19 mEq/l. 24-hour urinaryVMA excretion was normal at 1I0 mg. Bone marrowaspiration showed an active marrow with marked toxicchanges, and some evidence of iron and possibly folatedeficiency. Serum iron was 52 ,ug/100 ml, serum folate6 2 ng/ml, and serum B12 464 ,ug/ml. Serum totalbilirubin was <0*7 mg/100 ml. Serum glutamicoxoloacetic transaminase was 108 and glutamic pyruvictransaminase was 59 ,umol/pyruvate per 100 ml per hr.Serum albumin was 1 9 g/100 ml. Serum immuno-globulins were IgG 37 IU/ml, IgM 308 IU/ml, IgA 42IU/ml. Blood culture was sterile. Urinary amino acidconcentrations were in the upper limit of normal and noabnormal urinary organic acids were detected. Lungfunction tests (at the time of lung biopsy) showed thetotal static lung compliance to be 9 * 4 ml/cm H20, whichis within normal limits for this age for our laboratory.Cine swallow showed normal deglutition. Toxoplasmadye test was negative. Cytomegalovirus complementfixation titre was <4 and the rubella haemagglutinationinhibition titre <8. Complement fixation tests foradenovirus, herpes simplex, influenza A, B, and C,respiratory syncytial virus, and mycoplasma pneumoniaall showed a titre of <8. No precipitins to Aspergillusfumigatus were present.

At 5 months of age when chest x-ray showed diffuseopacities, most marked in the perihilar regions, a lungbiopsy was performed but the tissue appeared normalhistologically. After biopsy his condition fluctuated buthe remained very ill. He deteriorated further 3 weeksafter biopsy with recurrence of pyrexia and crepitationsat the lung bases, and was treated with a further course ofampicillin and cloxacillin and was started on prednisolone40 mg daily. Chest x-ray showed extensive confluentshadowing in both lungs. From this time he madesteady improvement, which was maintained when theantibiotics were stopped. This improvement wasconfirmed radiologically and the dose of prednisolonewas gradually reduced to 5 mg daily over a 6-week

period. After one week at this dose his cough returned,he began to vomit and lost weight. The respiratory rateincreased and crepitations were heard at the right lungbase. The dose of prednisolone was increased to 15 mgdaily with subsequent clinical improvement.

Pulmonary haemosiderosis. Case 24. Thelatter months of pregnancy of this child's mother werecomplicated by ulcerative colitis. She was born after anormal delivery at 37 weeks' gestation and weighed 2 * 85kg. Her condition at birth was satisfactory, but shesubsequently lost weight and had to be fed by nasogastrictube. The neonatal period was also complicated byseveral convulsions ofunknown aetiology. At the age of6 weeks she was admitted to a local hospital with failureto thrive, respiratory difficulty, and hepatomegaly. Atthis time she was extensively investigated. A chest x-rayshowed diffuse lung disease with bilateral mottling,mainly perihilar. She continued to deteriorate in spiteoftreatment with antibiotics, diuretics, and prednisolone,and was admitted to this hospital for further investigationin November 1971, at the age of 14 weeks.On examination she was a pale, thin, cyanosed baby

with pulse rate 180/min and respiratory rate 130/min.Heart sounds were normal with no murmurs. Therewas poor air entry in all lung areas but no adventitialsounds. The abdomen was distended and the liver edgewas palpable 10 cm below the rib cage and was firm inconsistency. The spleen edge was palpable 2 cm belowthe rib cage. There was generalized hypotonia.

Investigations here and at the referring hospitalincluded Hb 10*5 g/100 ml and white blood count13,000/mm3 of which 71% were neutrophils, 27%lymphocytes, and 2% monocytes. Serum immuno-globulins were IgG and IgA normal, IgM 87 IU/ml (highnormal). Arterial blood gases were Po2 37 numHg andPco2 43 mmHg. Chest x-ray showed poor aeration ofboth lungs with a bilateral air bronchogram. Heart sizewas normal. Respiratory function tests performed atlung biopsy gave a low total static compliance of only 3ml/cm I{20. ECG was within normal limits. Plasmaacid phosphatase was 4H 1 KA units. Sweat electrolytes,bone marrow examination, and an intravenous pyelogramwere normal. Serological tests for syphilis werenegative, a skeletal survey was negative, and liver biopsynormal.

Progress. Oxygen therapy resulted in temporaryimprovement. A lung biopsy from the lingula showeddiffuse thickening of alveolar walls with some histiocyticinfiltration and an increase of reticulin, collagen, andelastic fibrils. Brownish macrophages were present inalveoli which stained positively for iron with Perls'sprussian blue method for haemosiderin. Haemosiderinwas also present in the alveolar walls in larger amounts inthe interlobular septa (Fig. 4).With the diagnosis of possible idiopathic pulmonary

haemosiderosis in mind, a trial of a diet free of milkprotein was started, but she continued to deteriorate anddied 4 days after the lung biopsy. Necropsyexamination revealed infradiaphragmatic total anomalouspulmonary venous drainage into the porta hepatis.

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Pulmonary haemosiderosis. The alveolar walls are thickened and iron is present in macrophageswithin the alveoli and in interlobular septa. (Perls's. x 200.)

DiscussionExcept in the most critically ill child, open lung

biopsy appears to be a safe procedure. All thebiopsies were helpful, even though they were not alldiagnostic. Obtaining a normal biopsy in a patientwith pneumocystis pneumonia, for example, wouldbe unlikely, and therefore biopsy was felt to excludethis possibility. In Case 22, who was known tohave a ventricular septal defect, persistent ductusarteriosus, and persistent foramen ovale, theselesions were felt to be insufficient to account for thediffuse lung disease which he had; but the biopsysuggested that in fact the cardiac problem wasresponsible, and reinvestigation confirmed thepresence of a large left-to-right shunt. The lungdisorder improved considerably when the persistentductus arteriosus was ligated and the pulmonaryartery banded.The diagnostic yield is similar to that published in

the series oflung biopsies in adults with diffuse lungdisease reported by Scadding in 1970, where 66 openfung biopsies were carried out and 53 proveddiagnostic, 8 were of doubtful categorization, and 5were noncontributory.The histological findings ofour patients and of the

three series previously reported in children are setout in Table II.As can be seen from Table II, the causes of diffuse

lung disease in children are legion. They includeprimary lung conditions such as cryptogenicfibrosing alveolitis, idiopathic pulmonary haemo-siderosis, alveolar proteinosis, and it is not possibleto make any of these diagnoses with certaintywithout resort to a lung biopsy. The two formerare sometimes responsive to treatment withglucocorticoids, and in treatment of alveolarproteinosis steroids are said to be contraindicated(Larson and Gordinier, 1965). Sosman et al.(1957) have said that alveolar microlithiasis, anothercondition causing diffuse lung disease, can bediagnosed on the basis of chest x-ray appearancesonly. Classically, the features are of fine-grainedpulmonary infiltrations involving the lung diffusely,with some sparing of the extreme apices andbases. There is no known treatment for thiscondition.

Congenital lung infections, such as those causedby rubella, cytomegalovirus, and syphilis, may causediffuse lung disease, but these diseases are oftenassociated with other congenital abnormalities, and

FIG. 4.-Case 24.

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Open lung biopsy in children with diffuse lung disease 35TABLE II

Comparison of the diagnoses found in 3 previously reported series compared with present series

Present series Stringer et al. (1968) Weng et al. (1968) Toyama et al. (1971)

Cryptogenic fibrosing alveolitis 8 10 8 3Pulmonary haemosiderosis 2 1 1P. carinii 5Aspergillosis 1 1Blastomycosis 1Farmer's lung 2Methotrexate lung 1Pneumonitis/bronchiolitis 4 1 2Lipoid pneumonia 1Visceral larva migrans 1Choriocarcinoma 1Noncaseating granuloma 1Carcinoma of thyroid 1Hystiocytosis X 1Giant cell pneumonia 1Wilson-Mikity 1Emphysema 3No diagnosis 4 1

Total 24 16 16 11

can usually be excluded on the basis of appropriatevirological and serological studies.

Neoplastic infiltrations in acute leukaemia andhistiocytosis-X may cause diffuse lung disease.Weng et al. (1968) made a diagnosis of histiocytosisby lung biopsy. However, this diagnosis canusually be made by other investigations, such asskeletal survey and skin or lymph node biopsy, andlung biopsy is usually unnecessary. Stringer et al.(1968) reported carcinoma of the thyroid gland andchorion carcinoma as causing diffuse lung disease,both being diagnosed by lung biopsy.

Conditions such as cystic fibrosis of the pancreasand H-type tracheo-oesophageal fistula may causediff-use lung disease, but the history from thesepatients is often diagnostic.Pulmonary oedema secondary to pulmonary

venous obstruction, such as in total anomalouspulmonary venous drainage, may present with apicture suggestive of primary lung disease, as didCase 24. In this condition cardiomegaly may beabsent, though the ECG is usually abnormal withevidence of right atrial and right ventricularhypertrophy and RS reversal. In none of the otherseries did congenital heart disease masquerade as aprimary lung problem.

Other infections, such as miliary tuberculosis andgiant cell pneumonias associated with the commonexanthema, are also usually diagnosed on the basis ofthe history and other investigations, without resortto lung biopsy. Pulmonary fungal infections areusually confirmed on the basis of the appropriatesputum cultures, serological and skin tests, and lung

biopsy is seldom needed. Only one case ofblastomycosis and two cases of aspergillosis inchildren have been diagnosed at lung biopsy andpublished in America.

Cryptogenic fibrosing alveolitis describes aclinical and histological picture whicb may well, inthe light of further knowledge, include a variety ofdisorders. In this series 10 patients were thoughtto have the clinical features of cryptogenic fibrosingalveolitis but this was only confirmed in 8 by biopsy(to be reported).

We are grateful to the physicians of The Hospital forSick Children, Great Ormond Street, London, forpermission to report details of patients under their care.

REFERENCES

Larson, R. K., and Gordinier, R. (1965). Pulmonary alveolarproteinosis. Annals of Internal Medicine, 62, 292.

Scadding, J. G. (1970). Lung biopsy in the diagnosis of diffuse lungdisease. British Medical Journal, 2, 557.

Scadding, J. G., and Hinson, K. F. W. (1967). Diffuse fibrosingalveolitis. Thorax, 22, 291.

Sosman, M. C., Dodd, G. D., Jones, W. D., and Pillmore, G. U.(1957). The familial occurrence of pulmonary alveolarmicrolithiasis. American Journal of Roentgenology, 77, 947.

Stringer, R. J., Stiles, Q. R., Lindesmith, G. G., Meyer, B. W., andJones, J. C. (1968). Use of lung biopsy in diagnosis ofpulmonary lesions in children. American Surgeon, 34, 810.

Toyama, W. M., Reyes, C. N., Lawton, B. R., and Sautter, R. D.(1971). Open lung biopsy in infants and children. Archives ofSurgery, 103, 195.

Weng, T-R., Levison, H., Wentworth, P., Simpson, J., and Moes, C.A. F. (1968). Open lung biopsy in children. American Reviewof Respiratory Diseases, 97, 673.

Correspondence to Professor D. Hull, Department ofChild Health, City Hospital, Hucknall Road,Nottingham NG5 1PB.

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