Journal of Infection (199o) 21, 131-137
REVIEW Glucocorticoid therapy for severe Pneumocystis pneumonia
carinii
R. F. Miller and S. J. G. S e m p l e
University College and Middlesex School of Medicine, Middlesex Hospital, Mortimer Street, London, W C I N 8AA, U.K. Accepted for publication 29 March I99o Summary The majority of patients with AIDS and Pneumocystis carinii pneumonia respond to treatment with either high-dose cotrimoxazole or IV pentamidine. Glucocorticoids have been given as 'adjuvant' therapy in those patients who fail to respond to cotrimoxazole or pentamidine. This article discusses the role of glucocorticoids therapy in the treatment of severe Pneumocystiscariniipneumonia and reviews the evidence for their efficacy.
Introduction
Pneumocystis carinH pneumonia is the commonest life-threatening infection in patients with A I D S and accounts for up to 80 % of all respiratory episodes. T h e disease ranges in severity from mild infection with a normal chest X-ray and an indolent course, to severe pneumonia with respiratory failure requiring mechanical ventilation, when the mortality exceeds 90 %. T h e diagnosis is now more likely to be made at an earlier stage of the disease process than in the past, because of increased awareness amongst medical personnel and patients themselves and also because of the sensitivity of bronchoscopic and laboratory techniques now available. Despite these diagnostic advances and increased awareness, the mortality rate for P. carinii pneumonia remains at 5 - I o %.1 U p to 85 % of patients with pneumocystis pneumonia will respond to conventional therapy with IV pentamidine or high-dose co-trimoxazole. 2 Patients usually improve by day 5 of treatment, rather more slowly than with bacterial pneumonia. Reduction of dyspnoea, defervescence of fever and an improvement in arterial blood gas tensions will have occurred in the majority of patients by day 7 of treatment. 3 T h e chest X-ray abnormalities often take up to 2 or 3 weeks to resolve. Markers that stratify patients according to outcome would be of clinical importance in managing patients with pneumocystis pneumonia. Those with good prognostic indices could be treated with oral or nebulised therapy as outpatients, and only those with poor prognoses would need to be monitored in hospital. Based on patterns of symptoms and clinical findings, the degree of abnormality o f the chest X-ray, measurements of oxygenation and results of laboratory tests, attempts have been made to identify which patients with pneumocystis pneumonia are likely to have a poor outcome. ~-9 T h e factors that are associated with a poor prognosis are shown in Table I. These studies show oi63-4453/9o/o5oi31+o7 $o2,oo/o
© 199° The British Society for the Study of Infection
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T a b l e I Factors associated with a poor outcome from Pneumocystis carinii pneumonia On admission Dyspnoea and unproductive cough for more than 4 weeks Tachypnoea (respiratory rate > 3o/min) Recurrent P. carinii pneumonia (second or third episode) Poor oxygenation : PaO~ < 53 mmHg (< 7.0 kPa), (A- a) DO 2 > 3o mmHg (> 4'0 kPa)* Low serum albumin (< 35 g/l) Peripheral blood leucocytosis (> Io'8 × Io9/1) Marked chest X-ray abnormalities (diffuse bilateral interstitial infiltrates with or without alveolar consolidation) Elevated serum lactate dehydrogenase enzyme activity (> 3o0 IU/1) Following admission Co-pathogens in bronchoalveolar lavage fluid (e.g. Staphylococcus aureus) Neutrophilia (> 5 %) in bronchoalveolar lavage fluid Transbronchial biopsy specimens showing severe interstitial oedema (a measure of the severity of diffuse alveolar damage) Elevated serum lactate dehydrogenase enzyme levels that do not fall when specific antipneumocystis therapy is started * (A-a) DO~ = alveolar-arterial oxygen difference. that those patients with severe p n e u m o c y s t i s p n e u m o n i a at presentation do badly, and that there is no reliable predictive index that enables prospective identification of patients who are likely to have a poor disease course. A few patients with pneumocystis p n e u m o n i a will deteriorate despite treatment. F a c e d with a patient who is either deteriorating despite conventional therapy, or who is severely ill on admission, several therapeutic options are available once alternative diagnoses have been excluded or infection with P. carinii and a co-pathogen has been identified and appropriate t h e r a p y has been started.
Therapeutic options (I) U p to 90 % of patients who d o n ' t respond to high-dose co-trimoxazole will also fail to respond to IV p e n t a m i d i n e , so changing f r o m one d r u g to the other m a y not be o f benefit. Both drugs have slow m e a n response times; p e n t a m i d i n e in particular seems to be associated with a slow response and delay in i m p r o v e m e n t of oxygenationfl (2) T r e a t m e n t m a y be changed to second-line 'salvage' drugs such as eflornithine ( D F M O ) 1° or trimetrexate. 11 T h e r e is very little data on the use o f these drugs in this situation and there have been no controlled studies. It is of concern that there appears to be a very high early relapse rate following successful t r e a t m e n t of pneumocystis p n e u m o n i a with trimetrexate. 11 (3) An alternative strategy is to continue IV p e n t a m i d i n e or high-dose cotrimoxazole and to give ' a d j u v a n t ' t h e r a p y with glucocorticoids.
Rationale for glucocorticoid t h e r a p y Diffuse alveolar epithelial cell damage occurs in P. carinii p n e u m o n i a , 12 this is manifest clinically as increased permeability of the alveolar-capillary
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membrane. 1~ Gallium-67 lung scanning confirms the presence of an active alveolar inflammatory process, x4 Histologically P. carinii pneumonia is characterised by the development of an intra-alveolar foamy exudate within which lie large numbers of trophozoites and cysts, and this is associated with hyperplasia of type II pneumocytes, with or without the development of a hyaline membrane. 1~ It is these changes which are thought to be responsible for the deterioration in respiratory status which occurs during the acute disease. In the rat, recovery from P. carinii pneumonia is associated with a mononuclear cell infiltrate within the alveoli and the interstitial spaces of the lung and also with the development of interstitial fibrosis. 16 These mononuclear cells are implicated in the killing of P. carinii organisms. 17 T h e radiological abnormalities and pulmonary dysfunction associated with severe P. carinii pneumonia bear striking similarities to the Adult Respiratory Distress Syndrome (ARDS), and both have in common diffuse alveolar damage. 18-2° Patients with A R D S who fail to respond to appropriate therapy for their underlying conditions and who require mechanical ventilation for prolonged periods are known to develop pulmonary fibrosis. Open-lung biopsies performed on six patients with bronchoscopically confirmed P. carinii pneumonia who were deteriorating despite conventional therapy with IV highdose co-trimoxazole showed severe interstitial fibrosis. 21 Exactly how glucocorticoids might promote resolution of P. carinii pneumonia is unknown. It is likely that they reduce the inflammatory response to this infection, and steroid-induced reduction of chemotaxis and phagocytic activity of inflammatory cells and the depression of complement-mediated neutrophil activation may protect against inflammatory lung damage. Given the slow response times for IV co-trimoxazole and pentamidine, glucocortioids may act by diminishing the inflammatory response to severe pneumocystis infection and allow time for the antimicrobial agents to exert their effects. This theory is supported by the open-lung biopsy findings in a patient with P. carinii pneumonia who received high doses of methylprednisolone 2 days before biopsy. Instead of the intense interstitial mononuclear cell infiltrate usually seen, there were only a few inflammatory cells in the interstitiumfl 2 An alternative theory is that glucocorticoids might act by inhibiting phospholipase A 2 and so retard degradation of surfactantfl 3 Justification for the use of glucocorticoids in patients with P. carinii pneumonia is based both on anecdotal reports and open prospective trials. Folzer reported a 2o-year-old HIV-positive intravenous drug abuser with P. carinii pneumonia confirmed on transbronchial biopsyfl a Initially there was a response to Iv co-trimoxazole, but after 3 days it was discontinued because of a rash and worsening chest X-ray. Intravenous pentamidine was started and during the next 3 days there was improvement until a sudden deterioration necessitated mechanical ventilation on day 5 of pentamidine therapy. Openlung biopsy was performed to exclude a co-pathogen; this revealed only P. carinii with an intense inflammatory response. Intravenous methylprednisolone I25 mg b.d. was started and 6 h after the first dose there was a dramatic improvement in oxygenation. T h e patient was extubated 2 days later. He completed 8 days of IV methylprednisolone followed by 6 days 'tapering d o w n ' of the dose of steroid with oral prednisolone. Pentamidine was
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continued throughout the steroid therapy and an 18-day course was completed. T h e clinical recovery was mirrored by continued improvement in the chest Xray, and no secondary pathogens emerged. In a study by MacFadden et al., 25 IO patients with P. carinii pneumonia and respiratory failure (PaO~ < 6o m m H g breathing > 6o% oxygen via a face mask) were given methylprednisolone (in a dose of 4o mg, 6-hourly) for 7 days in addition to either IV pentamidine a n d / o r high-dose co-trimoxazole, eight similar patients were given antimicrobial therapy alone. Nine of the IO patients treated with methylprednisolone survived, compared with only two of the eight patients treated conventionally. Clinical improvement was evident within 2 days of starting steroid therapy and in none of the Io patients did clinical deterioration or recurrence of P. carinii pneumonia occur on stopping the methylprednisolone (phenomena previously reported to occur). ~6Although infectious complications might be expected to occur more frequently during steroid therapy of patients with A I D S , these were not apparent during the study. However, disseminated Herpes zoster developed in one patient 48 h after steroids had been discontinued. Oral candidiasis was present in all patients, but in none did progression occur during treatment. No noninfectious complications of steroid use were observed. Mottin et al., 2~ carried out an open prospective study in patients with severe pneumocystis pneumonia (PaO~ < 5 o m m H g , breathing room air). Fifteen patients received IV methylprednisolone ( 2 4 o m g / d a y for 3 days, i 2 o m g / d a y for 3 days and 60 m g / d a y for 3 days) in addition to treatment with IV high-dose cotrimoxazole. As controls, I3 patients with severe pneumocystis pneumonia were used; these patients had been treated with IV high-dose co-trimoxazole only and were historical controls. T h e two groups of patients were matched in terms of age, duration of symptoms prior to diagnosis and PaO 2 on admission. Eight of I3 control patients died, as did three of I5 steroid-treated patients, but in the group who received steroids the duration of fever and hypoxaemia was reduced. Necropsies were carried out on six of the eight control patients : all showed severe pulmonary fibrosis. Necropsies on two of the three steroidtreated patients who died did not show pulmonary fibrosis, but in one there was evidence of colonization with cytomegalovirus. Since these reports, the efficacy of methylprednisolone has been questioned. Clement et al., 28 carried out a prospective double-blind study of 4I patients with P. carinii pneumonia and hypoxaemia [PaO 2 breathing air < 50 m g H g (6"7 kPa)]. Patients were given either IV methylprednisolone (60 mg q.d.s., reducing over 8 days) or placebo, in addition to conventional therapy with IV pentamidine or high-dose co-trimoxazole. T h e r e were no significant differences between the two groups in the degree of hypoxaemia or levels of lactate dehydrogenase enzyme activity. Survival 8 weeks after treatment was Io out of I9 (52 %) in the group given methylprednisolone and I3 out of 22 (59 %) in the placebo group. Additionally there were no differences in survival based on the initial drug used to treat the P. carinii pneumonia (pentamidine three alive, one dead and co-trimoxazole 20 alive, i6 dead) or on the duration of treatment before starting methylprednisolone or placebo; less than 2 days treatment, methylprednisolone four alive, one dead, placebo four alive, one dead: after 2 or more days treatment, methylprednisolone six alive, eight dead,
Steroids and pneumocystis pneumonia
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placebo nine alive, six dead. It should be noted that 29 out of 4I (7I %) of all the patients received intervention after 2 or more days conventional therapyfl 8 H o w can these contrary studies be reconciled ? Clearly patient selection and the timing of glucocorticoid treatment may be factors. In the study by M a c F a d d e n patients were deteriorating rapidly and were enrolled in an open fashion; Mottin's study was also open, but used historical controls. Clement's study, although ' b l i n d ' , did not specify the pattern of deterioration in the patients and it included a sub-group of patients who had been unwell for some time and deteriorated late on after 7 - I o days of treatment. T h e might suggest that glucocorticoids are not effective in patients slowly deteriorating after several days of conventional therapy. Also the n u m b e r s of patients studied were small, and a type II error may have occurred in statistical analysis. Another factor that may be important in assessing response to treatment is the dose of methylprednisolone used. Other groups have used m u c h bigger doses with encouraging results. Methylprednisolone r o g daily was given in a pulse-dose fashion for 3 days in an open prospective study of 26 patients with P. carinii p n e u m o n i a and variable hypoxaemia, who were deteriorating despite conventional therapy. T w e n t y - t h r e e patients responded and recovered fully. 29 I m p r o v e m e n t s in PaO 2 were seen at 24-36 h, defervescence of fever was seen within 2 4 h , and in some patients i m p r o v e m e n t in oxygenation and defervescence of fever occurred within I2 h of the first dose of methylprednisolone. In all patients the chest X-ray rapidly improved. T h r e e patients failed to respond and died. No side effects were seen initially, but one patient became jaundiced 3 weeks after the methylprednisolone treatment. This was found to be due to reactivation of hepatitis B infection and may have been related to a transient increase in i m m u n o s u p p r e s s i o n caused by the steroid. With the knowledge that glucocorticoids may be useful in patients with P. carinii p n e u m o n i a who have deteriorated despite conventional therapy, and knowing it is not possible to identify prospectively those patients who will deteriorate, two questions remain to be answered. (i) Do glucocorticoids really have any beneficial effects when given to patients with P. carinii p n e u m o n i a who have already deteriorated on conventional therapy and who have developed respiratory failure ? If so, what is the effective dose and what morbidity is associated with this form of therapy ? (2) If glucocorticoids are given on presentation to all patients with P. carinii p n e u m o n i a (in addition to conventional therapy with either pentamidine or high-dose co-trimoxazole), is deterioration to respiratory failure prevented and is outcome improved ? Again, it will be important to know the morbidity associated with this regime. T h e answers to both these questions will only be provided by multi-centre prospective double-blind placebo-controlled studies. Until the results of such studies are available, what recommendations can be made if glucocorticoid therapy is contemplated? M a n y centres use methylprednisolone in patients with moderate to severe P. carinii p n e u m o n i a who are deteriorating despite conventional therapy, as manifest by persistent fever, increasing infiltrates on the chest X-ray and worsening hypoxaemia. As the dose regime and length of therapy are not well
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e s t a b l i s h e d - in t h e l i m i t e d n u m b e r o f p a t i e n t s s t u d i e d , doses o f 40 m g q.d.s. to 1 g daily h a v e b e e n u s e d - c u r r e n t a d v i c e w o u l d be to use b e t w e e n 250 m g a n d 1 g o f m e t h y l p r e d n i s o l o n e daily f o r 3 s u c c e s s i v e d a y s , w i t h o u t a n y s u b s e q u e n t ' t a p e r i n g d o w n ' . I n t h o s e p a t i e n t s w h o s e b l o o d gases are s l o w to i m p r o v e o r w h o s e f e v e r p e r s i s t s o n this r e g i m e , l o n g e r c o u r s e s o f u p to 5 d a y s m a y be n e c e s s a r y .
References I. Gazzard BG. Pneumocystis carinii pneumonia and its treatment in patients with AIDS. J Antimicrob Chemother I989; 23 (Suppl A): 67-752. Sattler FR, Cowan R, Neilson DM, Ruskin J. Trimethoprim-sulfamethoxazole compared with pentamidine for treatment of Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Ann Intern Med I988; IO9: 280-287. 3. Miller RF, Mitchell DM. Management of respiratory failure in patients with the acquired immune deficiency syndrome and Pneumocystis carinii pneumonia. Thorax I99o; 45: I4O-I46. 4. Brenner M, Ognibene FP, Lack EE et al. Prognostic factors and life expectancy of patients with acquired immunodeficiency syndrome and Pneumocystis carinii pneumonia. Am Rev Respir Dis I987; I36: II99-I2O6. 5. Kales CP, Murren JR, Torres RA, Crocco JA. Early predictors of in-hospital mortality for Pneumocystis carinii pneumonia in the acquired immunodeficiency syndrome. Arch Intern Med I987; I47: I413-I4,7. 6. EI-Sadr W, Simberkoff MS. Survival and prognostic factors in severe Pneumocystis carinii pneumonia requiring mechanical ventilation. Am Rev Respir Dis I988 ; I37: I264-I267. 7. Zaman MK, White DA. Serum lactate dehydrogenase levels and Pneumocystis carinii pneumonia: diagnostic and prognostic significance. Am Rev Respir Dis x985; *37 : 796-800. 8. Mason GR, Hashimoto CH, Dickman PS, Foutty LF, Cobb CJ. Prognostic implications of bronchoalveolar lavage neutrophilia in patients with Pneumocystis carinii pneumonia and AIDS. Am Rev Respir Dis *989; x39: '336-I4429. Gardner TD, Youle M, Hanson PJV, Griffiths PD, Collins JV, Gazzard BG. Diagnosis, treatment and outcome of pneumonia in the acquired immune deficiency syndrome. J Infect *989; x8: I I I - I I 7 . ,o. McLees BD, Barlow JLR, Kuzma RJ, Baringtang DC, Schecter PJ. Studies on successful eflornithine treatment of Pneumocystis carinii pneumonia (PCP) in AIDS patients failing conventional therapy. Third International Congress on AIDS, Washington, ,987 . (Abstr.) TH. 4.2: I55. , I. Allegra CJ, Chabner BA, Tuazon CU et al. Trimetrexate for the treatment of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. N Engl J Med I987; 317 : 978,985. I 2 . Yoneda K, Wuther PD. Experimental Pneumocystis carinii pneumonia in the rat: mechanism of alveolar injury. Br J Exp Pathol *98x ; 6z: 339-346. I3. O'Doherty M J, Page CJ, Bradbeer CS et al. The place of lung 99mTcDTP A aerosol transfer in the investigation of lung infections in HIV positive patients. Respir Med *989; 83: 395-4oI. I4. Miller RF. Nuclear medicine and AIDS. Eur J Nucl Med I99o; x6: IO3-II8. I5. Weber W, Askin F, Dehner L. Lung biopsy in Pneumocystis carinii pneumonia. A m J Clin Pathol I977; 67: I I - I 9 . ,6. Walzer PD, Yoneda K, Powell RD. Growth characteristics and pathogenesis of experimental Pneumocystis carinii pneumonia. Infect Immun *980; 27:928-937 • I7. Masur H, Jones TC. The interaction in vitro of Pneumocystis carinii with macrophages and L cells. J Exp Med I978; I47: *57-*70. ,8. Bachofen M, Weibel ER. Structural alterations of lung parenchyma in the adult respiratory distress syndrome. Clin Chest Med I982; 3: 35-56. I9. Spencer H. Pathology of the lung. 4th ed. Vol. *. New York: Pergamon Press, I985: 372-378 •
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20. Yoneda K, Walzer PD. Interaction of Pneumocystis carinii with host lungs: an ultra structural study. Infect Immun I98o; z9: 928. 2I. Fitzgerald W, Bevelaqua FA, Garay SM et al. The role of open lung biopsy in patients with the acquired immunodeficiency syndrome. Chest i987; 9x: 659-66I. 22. E1-Sadr W, Sidhu G, Diamond G e t al. High dose corticosteroids as adjunctive therapy in severe Pneumocystis carinii pneumonia. A I D S Res I986; z: 349-355. 23. Kernbaum S, Masliah J, Alandor LG, Bouton C, Christol D. Phospholipase activity of bronchoalveolar lavage fluid in the rat Pneumocystis carinii pneumonia. Br J Exp Pathol I983 ; 64 : 75-80. 24. Foltzer MA, Hannan SE, Kozak AJ. Pneumocystis pneumonia: Response to corticosteroids. J A M A I985; 253:979 (Letter). 25. MacFadden DK, Edelson JD, Hyland RH, Rodriguez CH, Inouye T, Rebuck AS. Corticosteroids as adjunctive therapy in treatment of Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome. Lancet z987; i: I477-t479. 26. Young LS. Clinical aspects of pneumocystosis in man: epidemiology, clinical manifestations, diagnostic approaches and sequelae. In: Young LS, Ed. Pneumocystis carinii pneumonia. New York: Marcel Dekker, i984: i39-i74. 27. Mottin D, Denis M, Dombret H, Rossert J, Mayaud C, Akoun G. Role for steroids in treatment of Pneumoeystis carinii pneumonia in AID S. Lancet I987 ; ii : 5 ~928. Clement M, Edison R~ Turner J et al. Cortieosteroids as adjunctive therapy in severe Pneumocystis carinii pneumonia. Am Rev Respir Dis I989; I39(4): Az5o. 29. Miller RF, Semple SJG. Pulse mega-dose methylprednisolone as adjuvant therapy for the treatment of Pneumocystis carinii pneumonia. Thorax I99o; 45: 3o5p.
REVIEW Glucocorticoid therapy for severe Pneumocystis pneumonia
carinii
R. F. Miller and S. J. G. S e m p l e
University College and Middlesex School of Medicine, Middlesex Hospital, Mortimer Street, London, W C I N 8AA, U.K. Accepted for publication 29 March I99o Summary The majority of patients with AIDS and Pneumocystis carinii pneumonia respond to treatment with either high-dose cotrimoxazole or IV pentamidine. Glucocorticoids have been given as 'adjuvant' therapy in those patients who fail to respond to cotrimoxazole or pentamidine. This article discusses the role of glucocorticoids therapy in the treatment of severe Pneumocystiscariniipneumonia and reviews the evidence for their efficacy.
Introduction
Pneumocystis carinH pneumonia is the commonest life-threatening infection in patients with A I D S and accounts for up to 80 % of all respiratory episodes. T h e disease ranges in severity from mild infection with a normal chest X-ray and an indolent course, to severe pneumonia with respiratory failure requiring mechanical ventilation, when the mortality exceeds 90 %. T h e diagnosis is now more likely to be made at an earlier stage of the disease process than in the past, because of increased awareness amongst medical personnel and patients themselves and also because of the sensitivity of bronchoscopic and laboratory techniques now available. Despite these diagnostic advances and increased awareness, the mortality rate for P. carinii pneumonia remains at 5 - I o %.1 U p to 85 % of patients with pneumocystis pneumonia will respond to conventional therapy with IV pentamidine or high-dose co-trimoxazole. 2 Patients usually improve by day 5 of treatment, rather more slowly than with bacterial pneumonia. Reduction of dyspnoea, defervescence of fever and an improvement in arterial blood gas tensions will have occurred in the majority of patients by day 7 of treatment. 3 T h e chest X-ray abnormalities often take up to 2 or 3 weeks to resolve. Markers that stratify patients according to outcome would be of clinical importance in managing patients with pneumocystis pneumonia. Those with good prognostic indices could be treated with oral or nebulised therapy as outpatients, and only those with poor prognoses would need to be monitored in hospital. Based on patterns of symptoms and clinical findings, the degree of abnormality o f the chest X-ray, measurements of oxygenation and results of laboratory tests, attempts have been made to identify which patients with pneumocystis pneumonia are likely to have a poor outcome. ~-9 T h e factors that are associated with a poor prognosis are shown in Table I. These studies show oi63-4453/9o/o5oi31+o7 $o2,oo/o
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T a b l e I Factors associated with a poor outcome from Pneumocystis carinii pneumonia On admission Dyspnoea and unproductive cough for more than 4 weeks Tachypnoea (respiratory rate > 3o/min) Recurrent P. carinii pneumonia (second or third episode) Poor oxygenation : PaO~ < 53 mmHg (< 7.0 kPa), (A- a) DO 2 > 3o mmHg (> 4'0 kPa)* Low serum albumin (< 35 g/l) Peripheral blood leucocytosis (> Io'8 × Io9/1) Marked chest X-ray abnormalities (diffuse bilateral interstitial infiltrates with or without alveolar consolidation) Elevated serum lactate dehydrogenase enzyme activity (> 3o0 IU/1) Following admission Co-pathogens in bronchoalveolar lavage fluid (e.g. Staphylococcus aureus) Neutrophilia (> 5 %) in bronchoalveolar lavage fluid Transbronchial biopsy specimens showing severe interstitial oedema (a measure of the severity of diffuse alveolar damage) Elevated serum lactate dehydrogenase enzyme levels that do not fall when specific antipneumocystis therapy is started * (A-a) DO~ = alveolar-arterial oxygen difference. that those patients with severe p n e u m o c y s t i s p n e u m o n i a at presentation do badly, and that there is no reliable predictive index that enables prospective identification of patients who are likely to have a poor disease course. A few patients with pneumocystis p n e u m o n i a will deteriorate despite treatment. F a c e d with a patient who is either deteriorating despite conventional therapy, or who is severely ill on admission, several therapeutic options are available once alternative diagnoses have been excluded or infection with P. carinii and a co-pathogen has been identified and appropriate t h e r a p y has been started.
Therapeutic options (I) U p to 90 % of patients who d o n ' t respond to high-dose co-trimoxazole will also fail to respond to IV p e n t a m i d i n e , so changing f r o m one d r u g to the other m a y not be o f benefit. Both drugs have slow m e a n response times; p e n t a m i d i n e in particular seems to be associated with a slow response and delay in i m p r o v e m e n t of oxygenationfl (2) T r e a t m e n t m a y be changed to second-line 'salvage' drugs such as eflornithine ( D F M O ) 1° or trimetrexate. 11 T h e r e is very little data on the use o f these drugs in this situation and there have been no controlled studies. It is of concern that there appears to be a very high early relapse rate following successful t r e a t m e n t of pneumocystis p n e u m o n i a with trimetrexate. 11 (3) An alternative strategy is to continue IV p e n t a m i d i n e or high-dose cotrimoxazole and to give ' a d j u v a n t ' t h e r a p y with glucocorticoids.
Rationale for glucocorticoid t h e r a p y Diffuse alveolar epithelial cell damage occurs in P. carinii p n e u m o n i a , 12 this is manifest clinically as increased permeability of the alveolar-capillary
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membrane. 1~ Gallium-67 lung scanning confirms the presence of an active alveolar inflammatory process, x4 Histologically P. carinii pneumonia is characterised by the development of an intra-alveolar foamy exudate within which lie large numbers of trophozoites and cysts, and this is associated with hyperplasia of type II pneumocytes, with or without the development of a hyaline membrane. 1~ It is these changes which are thought to be responsible for the deterioration in respiratory status which occurs during the acute disease. In the rat, recovery from P. carinii pneumonia is associated with a mononuclear cell infiltrate within the alveoli and the interstitial spaces of the lung and also with the development of interstitial fibrosis. 16 These mononuclear cells are implicated in the killing of P. carinii organisms. 17 T h e radiological abnormalities and pulmonary dysfunction associated with severe P. carinii pneumonia bear striking similarities to the Adult Respiratory Distress Syndrome (ARDS), and both have in common diffuse alveolar damage. 18-2° Patients with A R D S who fail to respond to appropriate therapy for their underlying conditions and who require mechanical ventilation for prolonged periods are known to develop pulmonary fibrosis. Open-lung biopsies performed on six patients with bronchoscopically confirmed P. carinii pneumonia who were deteriorating despite conventional therapy with IV highdose co-trimoxazole showed severe interstitial fibrosis. 21 Exactly how glucocorticoids might promote resolution of P. carinii pneumonia is unknown. It is likely that they reduce the inflammatory response to this infection, and steroid-induced reduction of chemotaxis and phagocytic activity of inflammatory cells and the depression of complement-mediated neutrophil activation may protect against inflammatory lung damage. Given the slow response times for IV co-trimoxazole and pentamidine, glucocortioids may act by diminishing the inflammatory response to severe pneumocystis infection and allow time for the antimicrobial agents to exert their effects. This theory is supported by the open-lung biopsy findings in a patient with P. carinii pneumonia who received high doses of methylprednisolone 2 days before biopsy. Instead of the intense interstitial mononuclear cell infiltrate usually seen, there were only a few inflammatory cells in the interstitiumfl 2 An alternative theory is that glucocorticoids might act by inhibiting phospholipase A 2 and so retard degradation of surfactantfl 3 Justification for the use of glucocorticoids in patients with P. carinii pneumonia is based both on anecdotal reports and open prospective trials. Folzer reported a 2o-year-old HIV-positive intravenous drug abuser with P. carinii pneumonia confirmed on transbronchial biopsyfl a Initially there was a response to Iv co-trimoxazole, but after 3 days it was discontinued because of a rash and worsening chest X-ray. Intravenous pentamidine was started and during the next 3 days there was improvement until a sudden deterioration necessitated mechanical ventilation on day 5 of pentamidine therapy. Openlung biopsy was performed to exclude a co-pathogen; this revealed only P. carinii with an intense inflammatory response. Intravenous methylprednisolone I25 mg b.d. was started and 6 h after the first dose there was a dramatic improvement in oxygenation. T h e patient was extubated 2 days later. He completed 8 days of IV methylprednisolone followed by 6 days 'tapering d o w n ' of the dose of steroid with oral prednisolone. Pentamidine was
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A N D S. J. G. S E M P L E
continued throughout the steroid therapy and an 18-day course was completed. T h e clinical recovery was mirrored by continued improvement in the chest Xray, and no secondary pathogens emerged. In a study by MacFadden et al., 25 IO patients with P. carinii pneumonia and respiratory failure (PaO~ < 6o m m H g breathing > 6o% oxygen via a face mask) were given methylprednisolone (in a dose of 4o mg, 6-hourly) for 7 days in addition to either IV pentamidine a n d / o r high-dose co-trimoxazole, eight similar patients were given antimicrobial therapy alone. Nine of the IO patients treated with methylprednisolone survived, compared with only two of the eight patients treated conventionally. Clinical improvement was evident within 2 days of starting steroid therapy and in none of the Io patients did clinical deterioration or recurrence of P. carinii pneumonia occur on stopping the methylprednisolone (phenomena previously reported to occur). ~6Although infectious complications might be expected to occur more frequently during steroid therapy of patients with A I D S , these were not apparent during the study. However, disseminated Herpes zoster developed in one patient 48 h after steroids had been discontinued. Oral candidiasis was present in all patients, but in none did progression occur during treatment. No noninfectious complications of steroid use were observed. Mottin et al., 2~ carried out an open prospective study in patients with severe pneumocystis pneumonia (PaO~ < 5 o m m H g , breathing room air). Fifteen patients received IV methylprednisolone ( 2 4 o m g / d a y for 3 days, i 2 o m g / d a y for 3 days and 60 m g / d a y for 3 days) in addition to treatment with IV high-dose cotrimoxazole. As controls, I3 patients with severe pneumocystis pneumonia were used; these patients had been treated with IV high-dose co-trimoxazole only and were historical controls. T h e two groups of patients were matched in terms of age, duration of symptoms prior to diagnosis and PaO 2 on admission. Eight of I3 control patients died, as did three of I5 steroid-treated patients, but in the group who received steroids the duration of fever and hypoxaemia was reduced. Necropsies were carried out on six of the eight control patients : all showed severe pulmonary fibrosis. Necropsies on two of the three steroidtreated patients who died did not show pulmonary fibrosis, but in one there was evidence of colonization with cytomegalovirus. Since these reports, the efficacy of methylprednisolone has been questioned. Clement et al., 28 carried out a prospective double-blind study of 4I patients with P. carinii pneumonia and hypoxaemia [PaO 2 breathing air < 50 m g H g (6"7 kPa)]. Patients were given either IV methylprednisolone (60 mg q.d.s., reducing over 8 days) or placebo, in addition to conventional therapy with IV pentamidine or high-dose co-trimoxazole. T h e r e were no significant differences between the two groups in the degree of hypoxaemia or levels of lactate dehydrogenase enzyme activity. Survival 8 weeks after treatment was Io out of I9 (52 %) in the group given methylprednisolone and I3 out of 22 (59 %) in the placebo group. Additionally there were no differences in survival based on the initial drug used to treat the P. carinii pneumonia (pentamidine three alive, one dead and co-trimoxazole 20 alive, i6 dead) or on the duration of treatment before starting methylprednisolone or placebo; less than 2 days treatment, methylprednisolone four alive, one dead, placebo four alive, one dead: after 2 or more days treatment, methylprednisolone six alive, eight dead,
Steroids and pneumocystis pneumonia
r35
placebo nine alive, six dead. It should be noted that 29 out of 4I (7I %) of all the patients received intervention after 2 or more days conventional therapyfl 8 H o w can these contrary studies be reconciled ? Clearly patient selection and the timing of glucocorticoid treatment may be factors. In the study by M a c F a d d e n patients were deteriorating rapidly and were enrolled in an open fashion; Mottin's study was also open, but used historical controls. Clement's study, although ' b l i n d ' , did not specify the pattern of deterioration in the patients and it included a sub-group of patients who had been unwell for some time and deteriorated late on after 7 - I o days of treatment. T h e might suggest that glucocorticoids are not effective in patients slowly deteriorating after several days of conventional therapy. Also the n u m b e r s of patients studied were small, and a type II error may have occurred in statistical analysis. Another factor that may be important in assessing response to treatment is the dose of methylprednisolone used. Other groups have used m u c h bigger doses with encouraging results. Methylprednisolone r o g daily was given in a pulse-dose fashion for 3 days in an open prospective study of 26 patients with P. carinii p n e u m o n i a and variable hypoxaemia, who were deteriorating despite conventional therapy. T w e n t y - t h r e e patients responded and recovered fully. 29 I m p r o v e m e n t s in PaO 2 were seen at 24-36 h, defervescence of fever was seen within 2 4 h , and in some patients i m p r o v e m e n t in oxygenation and defervescence of fever occurred within I2 h of the first dose of methylprednisolone. In all patients the chest X-ray rapidly improved. T h r e e patients failed to respond and died. No side effects were seen initially, but one patient became jaundiced 3 weeks after the methylprednisolone treatment. This was found to be due to reactivation of hepatitis B infection and may have been related to a transient increase in i m m u n o s u p p r e s s i o n caused by the steroid. With the knowledge that glucocorticoids may be useful in patients with P. carinii p n e u m o n i a who have deteriorated despite conventional therapy, and knowing it is not possible to identify prospectively those patients who will deteriorate, two questions remain to be answered. (i) Do glucocorticoids really have any beneficial effects when given to patients with P. carinii p n e u m o n i a who have already deteriorated on conventional therapy and who have developed respiratory failure ? If so, what is the effective dose and what morbidity is associated with this form of therapy ? (2) If glucocorticoids are given on presentation to all patients with P. carinii p n e u m o n i a (in addition to conventional therapy with either pentamidine or high-dose co-trimoxazole), is deterioration to respiratory failure prevented and is outcome improved ? Again, it will be important to know the morbidity associated with this regime. T h e answers to both these questions will only be provided by multi-centre prospective double-blind placebo-controlled studies. Until the results of such studies are available, what recommendations can be made if glucocorticoid therapy is contemplated? M a n y centres use methylprednisolone in patients with moderate to severe P. carinii p n e u m o n i a who are deteriorating despite conventional therapy, as manifest by persistent fever, increasing infiltrates on the chest X-ray and worsening hypoxaemia. As the dose regime and length of therapy are not well
I36
R. F. M I L L E R AND S. J. G. SEMPLE
e s t a b l i s h e d - in t h e l i m i t e d n u m b e r o f p a t i e n t s s t u d i e d , doses o f 40 m g q.d.s. to 1 g daily h a v e b e e n u s e d - c u r r e n t a d v i c e w o u l d be to use b e t w e e n 250 m g a n d 1 g o f m e t h y l p r e d n i s o l o n e daily f o r 3 s u c c e s s i v e d a y s , w i t h o u t a n y s u b s e q u e n t ' t a p e r i n g d o w n ' . I n t h o s e p a t i e n t s w h o s e b l o o d gases are s l o w to i m p r o v e o r w h o s e f e v e r p e r s i s t s o n this r e g i m e , l o n g e r c o u r s e s o f u p to 5 d a y s m a y be n e c e s s a r y .
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20. Yoneda K, Walzer PD. Interaction of Pneumocystis carinii with host lungs: an ultra structural study. Infect Immun I98o; z9: 928. 2I. Fitzgerald W, Bevelaqua FA, Garay SM et al. The role of open lung biopsy in patients with the acquired immunodeficiency syndrome. Chest i987; 9x: 659-66I. 22. E1-Sadr W, Sidhu G, Diamond G e t al. High dose corticosteroids as adjunctive therapy in severe Pneumocystis carinii pneumonia. A I D S Res I986; z: 349-355. 23. Kernbaum S, Masliah J, Alandor LG, Bouton C, Christol D. Phospholipase activity of bronchoalveolar lavage fluid in the rat Pneumocystis carinii pneumonia. Br J Exp Pathol I983 ; 64 : 75-80. 24. Foltzer MA, Hannan SE, Kozak AJ. Pneumocystis pneumonia: Response to corticosteroids. J A M A I985; 253:979 (Letter). 25. MacFadden DK, Edelson JD, Hyland RH, Rodriguez CH, Inouye T, Rebuck AS. Corticosteroids as adjunctive therapy in treatment of Pneumocystis carinii pneumonia in patients with acquired immunodeficiency syndrome. Lancet z987; i: I477-t479. 26. Young LS. Clinical aspects of pneumocystosis in man: epidemiology, clinical manifestations, diagnostic approaches and sequelae. In: Young LS, Ed. Pneumocystis carinii pneumonia. New York: Marcel Dekker, i984: i39-i74. 27. Mottin D, Denis M, Dombret H, Rossert J, Mayaud C, Akoun G. Role for steroids in treatment of Pneumoeystis carinii pneumonia in AID S. Lancet I987 ; ii : 5 ~928. Clement M, Edison R~ Turner J et al. Cortieosteroids as adjunctive therapy in severe Pneumocystis carinii pneumonia. Am Rev Respir Dis I989; I39(4): Az5o. 29. Miller RF, Semple SJG. Pulse mega-dose methylprednisolone as adjuvant therapy for the treatment of Pneumocystis carinii pneumonia. Thorax I99o; 45: 3o5p.
