Thorax, 1980, 35, 140-144

Mycoplasma pneumonia with fulminantevolution into diffuse interstitial fibrosisJ M KAUFMAN, C A CUVELIER, AND M VAN DER STRAETEN

From the Departments of Medicine and Pathology, State University Hospital, Gent, Belgium

ABSTRACT A fatal case of interstitial pneumonia caused by Mycoplasma pneumoniae withfulminant evolution into diffuse interstitial fibrosis is reported. Treatment with tetracycline andcorticosteroids failed to arrest the progress of the disease. Fatal Mycoplasma pneumoniaeinfections have been reported previously and some degree of pulmonary fibrosis has beendescribed in a few cases but as far as could be ascertained there are no other well-documentedcases of diffuse interstitial fibrosis with proved Mycoplasma pneumoniae infection.

Mycoplasma pneumoniae is a well-documentedand recognised cause of pneumonia, although inmost cases infection remains subclinical or limitedto upper respiratory tract involvement.'-4 Clinicaland radiographic features are inconstant and donot allow for differentiation from pneumoniascaused by other micro-organisms.5 6 Mycoplasmapneumoniae usually has a rather benign, self-limiting course. However, besides important extra-pulmonary complications such as haemolyticanaemia,7 8 myopericarditis,8-0 and neurologicalmanifestations,3 4severe and even fatal respiratorydisease from Mycoplasma pneumoniae has beenreported. The pulmonary complications includeunilateral and bilateral massive pneumonia,31' 2large unilateral and bilateral pleural effusions,3 11 13lung abscess,3 12 Swyer-James syndrome,14 andextensive interstitial pneumonia with severe hy-poxaemia.15-'7 Although exceptional, persistenceof respiratory symptoms after Mycoplasma pneu-moniae infection has been reported,' 8 and on afew occasions some degree of fibrosis has beendemonstrated at necropsy'7-19 but this conditionhas not yet been well documented.

Case report

Sixteen days postpartum, a previously healthy31-year-old woman complained of rhinitis andgeneral malaise followed the next day by chills,fatigue, and non-productive cough. On the thirdnight she woke up with mild dyspnoea which

Address for reprint requests: Dr JM Kaufman, Department ofMedicine, State University Hospital, Gent, Belgium.

became more pronounced during the morning.She also complained of vertigo and anorexia, andvomited once. The next morning she becameseverely dyspnoeic and was admitted to a localhospital. Arterial blood gas analysis revealed acarbon dioxide tension (Pco2) of 35 mmHg and anoxygen tension (Po2) of 75 mmHg while breathing4 litres of oxygen per minute. The chest radio-graph showed patchy lobular shadows involvingboth lower zones (fig 1). The patient was trans-ferred to the intensive care unit of the UniversityHospital, with tachypnoea (36 to 40/min), a tem-perature of 37 50C, and slightly diminished breath

Fig 1 Chest radiograph (PA) on admission tohospital shows patchy lobular infiltration involvingboth lower zones.

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Mycoplasma pneumonia with fulminant evolution into diffuse interstitial fibrosis

Fig 2 Chest radiograph (PA) on the fifteenth day inhospital shows diffuse mottling of both lungs.

sounds at the right base. Arterial blood gases onambient air revealed a Pco2 of 38 mmHg and aP02 of 66 mmHg. The erythrocyte sedimentationrate was 100 mm/h, white cell counts 6800/mm3with 70% neutrophils. Treatment was started withdoxycycline intravenously, 200mg daily, and onedose of 25 mg prednisolone.The next day the patient seemed to improve;

chest radiograph was unchanged. During the nexttwo days, she had only mild dyspnoea but hertemperature rose to 390C and radiographs showedslightly increased infiltration of both bases.A technetium perfusion lung scan showed an

area of diminished perfusion in the left paracar-

diac area, and on the fourth day in hospital, inaddition to doxycycline, heparin was started in a

dose of 37500 units/day by continuous infusion.On the fifth day the patient's condition deterior-ated quickly, with extreme dyspnoea and severe

respiratory distress. Arterial blood gas analysisbreathing 10 litres/min with an oxygen mask,showed pH 7-58, Pco2 29-5 mmHg, and P0234.5 mmHg. The patient became apnoeic and was

immediately intubated and ventilated. Doxycy-cline and heparin were continued, and in additionthe patient received high doses of betamethasone.For two days there was a progressive improvementwith satisfactory blood gas values on PEEP 10 cmH20 and 50% inspired oxygen initially, reduc-ing to 25% later on. The chest radiograph showedprogressive changes, with some early reticularinfiltrates in the upper zones. The white cell was

between 15 000 and 20 000/mm3. On the tenthday in hospital the situation deteriorated again

progressively. The patient went into graduallyincreasing alveolo-capillary block. Successive chestfilms showed increasing interstitial infiltrates allover the lungs with massive, patchy, confluentshadows in the lower parts and more reticularshadows in the upper parts with a picture suggest-ing advanced interstitial pneumonitis (fig 2).Sputa were purulent, but frequent cultures

for aerobic and anaerobic bacteria, mycobacteria,and fungi were all negative. The patient died onthe seventeenth day in hospital. At that time theblood gas values ranged around 90 mmHg Pco2and 60 mmHg P02 despite ventilation. In oneweek, from the fourth to the tenth hospital day,the titre of complement fixing antibody for Myco-plasma pneumoniae rose from less than 1/4 to1/128. No cold agglutinin titre could be demon-strated. Further studies on paired sera were nega-tive for Coxsackie 1-6, Varicella, influenza A-B,para-influenza 1-3, adenovirus, psittacosis, orni-thosis, and respiratory syncitial virus.

NECROPSYThe left lung weighed 800 g and the right lung1100 g. They both had a similar external aspectwith moderate reticular anthracosis and a purple-grey to reddish appearance. The surface wasnodular with fibrous pleura thickening. The lungfelt firm and the cut surface was reddish-greyand white, intersected by round microcysts andwhite nodules. No purulent material could beexpressed.On microscopy similar changes were found in

all the lobes. The sections made of formalin-fixedand paraffin-embedded lung tissue were stainedwith haematoxylin-eosin, PAS, Masson's tri-chrome, and reticulin. They showed a diffuse inter-stitial fibrosis (fig 3). The bronchioles were groupedin nodules, dilated and covered with a metaplasticstratified, flattened or squamous epithelium. Someshowed cystic dilatation and contained mucus,occasional giant cells, histocytes, polymorph leu-cocytes, and monocytes.

Severe fibrosis was seen in the thickened inter-alveolar septa and around the bronchioles. Thefibrous tissue consisted of young fusiform fibro-blasts which formed collagen. Inside the fibroustissue it was possible to distinguish small haemor-rhages, oedema fluid, and the alveolar capillarieswhich were increased in size and number andsurrounded by a cellular infiltrate. Within thefibrotic interstitial tissue the presence of mono-cytes and histocytes was observed. The alveolarwalls were covered by cuboidal cells with abun-dant, foamy cytoplasm with round vesicular

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¶'¶4,

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Fig 3 Severe interstitial fibrosis with fibroblast proliferation and monocellular infiltrate. Masson'strichrome stain, original magnification X 140.

nuclei. Some had desquamated into the lumen.The alveoli were filled with a homogenous exu-date, haemosiderin laden macrophages, polymorphleucocytes, erythrocytes, and giant cells (fig 4).Fibrin was seen only occasionally. The pleurawas thickened by bundles of collagen fibres.

Discussion

Mycoplasma pneumoniae has been mentioned asa possible cause of interstitial fibrosis20-22 but onlyin a few cases has some degree of fibrosis been re-ported.17-19 There are no well-documented casesin which evolution of a Mycoplasma pneumoniaepneumonia into diffuse interstitial fibrosis has beendescribed. The mechanisms leading to the patho-logical changes in diffuse interstitial fibrosis arewell known but not specific. The alterations canbe the result either of direct interstitial involve-ment or, as in this case, of a primary intra-alveolar process.20 23-27 The pneumocytes aredesquamated into the alveolar lumen. This is fol-lowed by exudation and incorporation of the exu-

date into the alveolar walls. Afterwards, fibro-blast proliferation starts between the sixth andninth day and gives rise to more organised andmature fibrous tissue. The alveolar lining epi-thelium is changed into type 2 pneumocytes andthe bronchiolar lining epithelium grows into therespiratory bronchiole which causes squamousmetaplasia.Numerous different agents are known to cause

diffuse interstitial fibrosis. It may follow radiationtherapy, oxygen toxicity, anti-neoplastic drugs,paraquat poisoning, inhalation of organic ormineral dust and toxic fumes. It is also seen asa terminal phase of sarcoidosis, collagen diseases,miscellaneous occupational diseases and otherinterstitial pneumonias. Infectious diseases havealso been implicated including bacterial, viral,fungal and parasitic infections. In our case, therewas a significant rise in M pneumoniae comple-ment fixation titre from 1/4 to 1/128 and mostof the other possible aetiological agents couldeasily be excluded.Oxygen toxicity may have been a factor in our

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Mycoplasma pneumonia with fulminant evolution into diffuse interstitial fibrosis

spE,[x sEAt _ :~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~~..

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Fig 4 Alveoli covered by cuboidal pneumnocytes. Thealveolar lumen is filled with macrophages, polymorphleucocytes, erythrocytes, and giant cells. Masson's trichrome stain, original magnification X360.

case, though this seems very unlikely. Indeed, ourpatient had been ventilated for less than 24 hourswith a gas mixture containing high oxygen con-centrations (maximal concentration of 66% oxy-gen) and at that time there was already diffuseradiological involvement of both lungs. The patho-logical findings in this patient could only havebeen provoked by prolonged administration ofhigh oxygen concentrations.28-30

Although not well documented previously, theassociation of pulmonary fibrosis with Myco-plasma pneumoniae infection is not surprising,and intermediate stages such as desquamatic inter-stitial pneumonia have indeed been describedbefore.17-19 31

Some authors suggest that cell-mediated immunemechanisms could be involved in severe cases ofmycoplasma pneumonia.8 1" It is, however, notnecessary to postulate an immunological mech-anism to explain the pathological changes ob-served in our patient, by analogy with oxygen andparaquat poisoning which can result in the same

histological picture without an immunologicalreaction. Intensive steroid therapy was not able toinfluence the course but administration wasstarted only on the eighth day of illness. The lackof response to adequate therapy with high dosesof tetracycline in this case is an interesting butnot unique feature: resistance of Mycoplasmapneumoniae infections to tetracycline has beenreported previously, and it is known that medica-tion is effective mainly when administered earlyin the course of the disease.' 2 7 32High doses of corticosteroids should probably

be considered in those cases of severe Mycoplasmapneumoniae pneumonia that do not improve afterthe fifth day from clinical onset. If started earlyenough steroid therapy could possibly influencefibroblast proliferation and prevent evolution intochronic or even fatal pulmonary fibrosis .

We thank Professor H Spencer for giving us hisvalued opinion on the pathological findings in thispatient.

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