Pneumocystis carinii Pneumonia in Patients with Systemic Lupus Erythematosus CHONG-KIN LIAM and FLORENCE WANG Department of Medicine, University Hospital, Faculty of Medicine, University of Malaya, 59100
Kuala
Lumpur, Malaysia
At the
University Hospital, Kuala Lumpur, Malaysia, nine patients with systemic lupus erythematosus (SLE) were treated for Pneumocystis carinii pneumonia (PCP) between January 1987 and December 1988. When they developed PCP all the patients’ SLE disease course was active and eight of them were on prednisolone. Four of these eight patients were also receiving cyclophosphamide. Patients who were on more intensive immunosuppressive
therapy were found to develop more severe PCP. All the patients except one were treated with high-dose cotrimoxazole. Four patients responded to antipneumocystis treatment and survived, while PCP was responsible for the death of the five non-survivors. Key Words: Pneumocystis carinii pneumonia SLE
Introduction Patients with systemic lupus erythematosus (SLE) are prone to opportunistic infections by bacteria, fungi, viruses and parasites’-’. The susceptibility to infection is increased when the disease is active. This may in part be due to the use of immunosuppressive therapy. Pneumocystis carinii pneumonia (PCP) is a serious and life-threatening complication of therapy associated with immune suppression 6,7. SLE patients, especially those who are receiving immunosuppressive therapy, are among those at risk of developing pCpl,7.’. This diffuse progressive pneumonia should be suspected when such patients develop unexplained respiratory symptoms and chest radiograph changes. This paper reports our experience with PCP in nine SLE patients.
Patients and methods From June 1974,
before the involvement was considered to be due Such investigations included microbiological studies, biochemical and serological tests, tissue biopsies, arterial blood gas analysis and lung function tests. The severity of the illness was judged by the number of systems involved and according to a set of criteria previously described by us &dquo;’. Patients with minor symptoms were treated symptomatically. Ill patients were initially treated with 60-80 mg oral prednisolone a day. The dose of prednisolone was then reduced gradually at monthly intervals as the activity of SLE lessened. In some patients prednisolone could be discontinued but those with residual symptoms stayed on a maintenance dose equivalent to 5 mg prednisolone a day. Patients who were toxic and very ill with multisystem involvement were given bolus intravenous methylprednisolone at 1 g daily for 3 consecutive days. This was sometimes repeated after 3-4 weeks when the patient was still very ill. Oral cyclophosphamide at 2 mg/kg/day was added when patients had not shown adequate improvement of renal involvement after 3 months. When there was exacerbation of SLE with multisystem involvement, oral prednisolone was resumed as described ant cyclophosphamide later when response was. inadequate, when persistent inflammation in the was confirmed by renal causes
patients
with SLE
were
studied pro-
spectively at the University Hospital, Kuala Lumpur, Malaysia. Patients were referred from all parts of the country when their illness
was
referred, generally ~ft~r parti~i
severe, or were selftreatment elsewhere or
when there was severe renal involvement. Only patients who fulfilled criteria for the of SLE according to the American Rheumatism Association’ were accepted into the study. Those who were clinically SLE were followed up with the SLE patients and were admitted into the SLE register when they fulfilled the criteria for the diagnosis of SLE. Patients with any target organ involvement were investigated to exclude other treatable
to SLE.
biopsy. Patients were suspected to have PCP when despite being on immunosuppressive therapy for SLE they developed inordinate dyspnoea, fever and non-productive cough with minimal chest associated with chest radiograph changes and respiratory failure that were not commensurate with the chest signs. The diagnosis of PCP
Correspondence: Liam Chong-Kin, M.B.B.S., M.R.C.P. (UK).
was
confirmed when the cysts of P. carinii
379
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were
found in pulmonary secretions by Gomori’s methenamine silver stain &dquo;. Diagnostic procedures included fibre-optic bronchoscopy with broncho-alveolar lavage (BAL) and bronchial brushing, tracheal aspirations via endotracheal tube while the patient was on mechanical ventilatory support, and induction of sputum production by inhalation oaf 3% saline. Fibre-optic bronchoscopy with the Olympus fibreoptic bronchoscope BF-10 was performed under local anaesthesia with parenteral sedation with midazolam. After inspection of the airways the tip of the bronchoscope was wedged into a subsegmental bronchus in the region of greatest radiological abnormality or in an anterior subsegment of the right middle lobe if the radiological changes were diffuse and bilateral. BAL was performed by instillation of sterile normal saline (100 ml) at room temperature in aliquots of 20 ml. Suction was then applied until at least half of the volume was collected in a secretion trap. Sheathed catheter bronchial brushings were performed with sheathed cytology brush BC-5C. The brushing material was smeared in a sinuous fashion over a 4 x 2 cm area on four glass slides, air dried and delivered without delay to the microbiologist for staining. Half of the lavage fluid was sent for staining and culture of organisms. The other half of the BAL sample was centrifuged at 3000 rpm for 5 min and the resulting deposit was spread onto several glass microscope slides and air dried. Transbronchial lung biopsy was attempted in two patients but was unsuccessful in both patients. Sputum was induced as described by Bigby ~~ ai. 12. The patient was fasted for at least 4 h before the induction. After cleaning teeth, gums and oral cavity by brushing and gargling with tap water, the patient inhaled a mist of 3 ~lo saline, generated by an ultrasonic nebulizer (Mistogen, model EN 145, Oakland, CA, USA) during tidal breathing for 10-20 min. The mask was removed, and the patient was instructed to breathe deeply three or four times keeping the mouth open, and then to cough forcefully, leading to expectoration. At least three aliquots of sputum were collected. If little sputum was produced, the induction time was extended by 5-Ifl min. Centrifugation was used to concentrate the sputum specimen to make it easier to detect the ~’. ~c~rit~~~ cysts. Tracheal secretions were obtained by suction through the endotracheal tube with a mucus extractor when patients with respiratory failure were on mechanical
ventilatory support. All preparations were stained to identify P. carinii cysts by means of Grocott’s modification of Gomori’s methenamine silver stain, the result of which was ready within several hours. All specimens were also stained with Ziehl-Neelsen stain for mycobacteria. Cultures were performed for mycobacteria and fungi. Aerobic
and anaerobic cultures for pyogenic bacteria were also performed. Facilities for culture of legionella and cytomegalovirus were not available. Blood cultures for bacteria and fungi were performed. Serological tests for legionella and cytomegalovirus were also carried out. Data regarding the clinical features, activity of SLE at the time of diagnosis of PCP, immunosuppressive therapy, chest radiograph changes, diagnostic procedures, antipneumocystis treatment and the outcome were
reviewed.
Results Since June 1974 patients with SLE have been seen either in the wards or in the clinics and followed up by one of us (FW) at the SLE clinic, initially at close intervals; as their disease condition improved, patients were seen at less frequent intervals. Patients from out of town were also followed up in the clinic. From June 1974 until December 1986, 416 patients with SLE had been seen at our hospital. Out of these, 69 patients had died and 82 had defaulted. The rest were on regular follow-up in the SLE clinic. From January 1987 to December 1988, 86 new cases of SLE were seen. Between January 1987 and December 1988, a total of 351 new and follow-up patients with SLE were seen at our hospital. Among those who needed hospitalization, some were new cases, and some were readmissions for exacerbation of SLE and for other problems not directly related to SLE. Of these 351 patients, nine developed PCP. During the same period there were 66 other cases of microbiologically confirmed F~F’, all of which occurred in patients with leukaemias who were on cytotoxic
chemotherapy. The overall racial distribution of SLE patients seen the University Hospital were Chinese 78.3%, Malay 17.2% and Indian 4.5~’~’~. The male to female ratio
at
was
1:1 ~.
All nine patients who developed PCP in this study were Chinese and all were females. The average age of these nine patients was 27 years, with a range of 14-34 years. Five patients had had SLE for several years (i.e. 2, 5, 6, 7 and 11 years, respectively) and were being treated for relapse of the disease. SLE was newly diagnosed in the other four patients ~i.~, 1, 2, 3 and 5 months, respectively). The SLE of all nine patients was active when they developed PCP. Eight patients were receiving prednisolone in doses ranging from 10 to 60 mg daily. Four of them were also on oral cyclophosphamide at 100 mg daily. One patient was not on any treatment except for some traditional Chinese medication. The clinical features of these patients at the time of diagnosis of PCP are summarized in Tables I and II, along with immunosuppressive therapy during the 1
380
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Table I
Clinical data
on
SLE
patients with PCP
who survived.
AaP°2: alveolar-arterial oxygen difference; ANA: antinuclear antibody titre; BAL: broncho-alveolar lavagt; BB: bronchial brushing; C3/C4: complement 3 level (normal 66-130 mg/dl) and complement 4 level (normal 20-60 rn,gld~~; CXR: chest X-ray; iv: intravenous; PCP: Pneumocystis carinii pneumonia; TS: tracheal secretions; wbc: white blood cell.
month preceding PCP, the total white cell count and lymphocyte count at the onset of serum levels oaf complement 3 and 4 at the time of diagnosis of PCP, antinuclear antibodies, serum creatinine, initial chest radiograph changes, initial alveolar-arterial oxygen difference, diagnostic procedures, co-existing infections and antipneumocystis treatment. Eight patients had symptoms of PCP for a week or less (average 4.5 days) before the diagnosis of PCP was made. Dyspnoea, fever, non-productive cough and
crepitations on lung auscultation were the most common initial and of PCP (Table 111). While the white cell counts of the patients varied when they developed PCP, eight patients had lymphopenia ~i,~, lymphocyte count less than 1.5 x l~~/l~. The differential white cell count of one patient around the time when she developed PCP was not performed. The mean lymphocyte count of patients who survived was 0.47 x 10’/l while that of the non-survivors was 0.48 x 10’/I. The serum creatinine of six patients
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Table ~~
Clinical data
on
SLE
patients who died of PCP.
alveolar-arterial oxygen difference; ANA: antinuclear antibody titre; BAL: broncho-alveolar lavage; BB: bronchial brushing; C3/C4: complement 3 level (normal 66-130 mg/dl) and complement 4 level (normal 20-W’mg/dl); CXR: chest X-ray; iv: intravenous; PCP: Pneumocystis carinii pneumonia; TS: tracheal secretion; wbc: white blood cell.
AaP02:
382
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Table III
Common initial symptoms and
died before intravenous administration of the drug could be commenced. Patient 7 died soon after the diagnosis of PCP was confirmed and before antipneumocystis treatment could be instituted. Pentamidine was not
signs of P. carinii
pneumonia.
available. Patients who were on cyclophosphamide had the drug discontinued upon diagnosis of PCP. However, the dose of prednisolone could not be reduced for any of the patients because of the activity of their SLE at the time PCP was diagnosed. The clinical condition of four patients improved with the treatment of PCP. Cotrimoxazole for patient 1 had to be discontinued after 13 days because of deterioration of her renal function. Treatment was given to patient 4 for only 7 days because she developed a drug rash. Her pneumonia had already improved by then and her clinical condition did not deteriorate after discontinuation of cotrimoxazole. No follow-up bronchoscopy was performed on the patients after institution of antipneumocystis treatment. PCP was the direct cause of death in the five non-survivors. Permission for autopsy was declined in all the non-surviving cases. Co-existing infections confirmed by bacteriological methods included pneumonia due to Mycobacterium tuberculosis, Klebsiella ozaenae, Pseudomonas aemginosa and Streptococcus pneumoniae. Co-existing infections occurred with the same frequency in the survivors and non-survivors. Serological titres for legionella and cytomegalovirus were not elevated in any of the patients.
(patient 2 and all the patients in Table II) was elevated when PCP was diagnosed and before treatment with ~~tri ~xazrale
was commenced. Patients 5, 6, 7, 8 and 9 (Table II), who
on the whole intensive immunosuppressive therapy, developed more extensive PCP as seen on their chest radiographs compared to patients 1, 2, 3 and 4 (Table I) who either were not on immunosuppressive therapy or were receiving less intensive immunosuppressive were on more
therapy. Initial arterial blood gas measurements were performed when the patients were either breathing room air or receiving supplemental oxygen through face masks delivering ~~-5t~~1~ oxygen. The severity of the pneumonic process was also reflected by the initial alveolar-arterial oxygen difference, which was higher for patients with more extensive radiographic changes. The diagnostic material and pulmonary secretions from all nine were obtained during life. The diagnosis of PCP in six patients was made after the detection of .F’. carinii organisms by fibre-optic bronchoscopic procedures. In another two patients P. carinii was present in tracheal secretions obtained by endotracheal tube suction when they were on ventilators for respiratory failure resulting from PCP. In the last patient, P. carinii was demonstrated in the expectorated sputum induced by inhalation of nebulized 3% saline. Eight patients were treated with oral and/or intravenous
Discussion
well-recognized pulmonary pathogen in immunocompromised hosts. PCP is a significant and life-threatening complication of therapy associated with immune suppression’,’. Among patients at risk are those with collagen vascular disease, especially if they are receiving immunosuppressive therapy 1,7,8. Impaired cellular immunity appears to be a major risk factor 14, 15. T cells are thought to release lymphokines, which activate alveolar macrophages and/or recruit and activate
P. carinii is
trimethoprim-sulphamethoxazole (cotrimoxazole).
Patients who were able to tolerate oral therapy were given trimethoprim (20mg/kg/day) and sulphamethoxazole (100 mg/kg/day) in four equal doses. Patients who had severe PCP received intravenous trimethoprim (15 mg/ kg/day) and sulphamethoxazole (75 mg/kg/day) in four equal doses. The doses were adjusted when renal function was impaired. Two patients (patients and 2) were given oral cotrimoxazole the treatment. because they were not ill. Cotrimoxazole was initially given intravenously to patients 3 and 4 but was subsequently administered orally once their clinical conditions had improved. Only patient 5 received cotrimoxazole intravenously for the whole treatment period of 14 days. For patients 6 and 9 oral cotrimoxazole was replaced by the intravenous form when their clinical status deteriorated. Patient 8 was on oral cotrimoxazole when her condition took a turn for the worse and she
a
monocytes to kill pneumocystis. Cell-mediated immunity is suppressed by high-dose corticosteroids 16,!7 and
cyclophosphamide&dquo;.
SLE itself is associated with
a
rang of T-cell defects that may be primary or secondary to anti-’~-~~il antibodies 19. In addition, deficient natural killer (NK) cell activity has been reported in patients with active lupus20. This probably explains why one of our patients who was not on any known immunosuppressive therapy and one who was on only 1 t~ m,~ prednisolone daily developed PCP. However, the activity of SLE has been found to be a risk factor for infection in some but not all studies 1,21,22. It is not surprising that our patients on more intensive 383
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immunosuppressive therapy developed more severe PCP. Intensive immunosuppressive therapy seems to be a poor prognostic factor, as this was associated with higher mortality. However, the difference in the degree of immunosuppression between the survivors and nonsurvivors was not reflected by the mean lymphocyte counts of the two groups of patients. This could be due to the small number of patients in this study. Hellmann and co-workers’ have found a strong correlation between immunosuppressive therapy and death from infections in patients with SLE. Therefore, when patients with SLE develop PCP, the question arises as to whether immunosuppressive therapy should be reduced or discontinued with possible exacerbation of SLE activity. Some authors 23, 24 recommend tapering of corticosteroids and other immunosuppressive therapy as much as the underlying disease allows to enable the host to develop an immunological response to the infection. It is not always possible to do this, especially when the patient is suffering from active SLE with multisystem involvement at the time of diagnosis of P~P.. Patients with renal insufficiency are known to have impaired immune response&dquo;. This may enhance the susceptibility to PCP in our SLE patients and could have accounted for the higher fatality among our SLE patients who had impaired renal function. The clinical manifestations of PCP in our patients were the same as described elsewhere~, with dyspnoea, fever and non-productive cough as the most frequent initial symptoms. All except one of our patients with SLE had symptoms of PCP for a week or less (average 4.5 days) before the diagnosis was made. Other investigators 26 have found that the duration of prodromal symptoms of PCP in patients with diseases requiring immunosuppressive therapy is shorter compared to that in patients with the acquired immunodeficiency syndrome (AIDS). Patients with AIDS had symptoms for a mean of 28 days before diagnosis, while patients with other immunosuppressive diseases had symptoms for a mean of 5 days. Untreated, pneumocystis pneumonia almost always runs a progressive and fatal courses. With appropriate chemotherapy ~(3-~~~~ of patients recover from this infection 15. High-dose cotrimoxazole has been the initial treatment of choice for PCP since 1978 when Hughes and co-workers 28 found it to be equally effective as the more toxic pentamidine. Intravenous treatment is recommended for the severely ill patient 29. A normogram is available to make dose adjustments in patients with impairment of renal function&dquo;. Pentamidine is an alternative drug for patients who develop adverse reactions to cotrimoxazole. Unfortunately, pentamidine was not locally available for use in our patients. All our patients were suffering from active SLE when they developed PCP. As many patients with active SLE *
also suffer from lupus nephritis with impaired renal function 31. 32, it is essential to confirm the diagnosis of PCP before initiation of therapy that may further worsen the renal function 33, 34. Although P, carinii is the most common cause of diffuse progressive pneumonia in the immunosuppressed patient&dquo; it must be differentiated from lupus pneumonitis, pulmonary oedema, occult intrapulmonary haemorrhage and other pulmonary infections 36, 37. Cytomegalovirus is a commonly identified co-existing infection with PCP and the frequency of dual infections with P. carinii and cytomegalovirus has been reported to be between 10 and 71 % &dquo;. Co-existing bacteria and other fungal infections may also be present. This underscores the need for thorough microbiological studies to determine whether any other treatable infection co-exists with PCP. The failure to make an early diagnosis of an opportunistic infection occurs when the infection simulates active SLE and when the possibility of an opportunistic infection is not thoroughly investigated 4. If any diagnostic procedure is contemplated in a SLE patient with pneumonitis it should be done early, preferably before the administration of antibiotic therapy, to ensure maximum
diagnostic yield.
Acknowledgements The authors would like to thank Associate Professor T.S. Soo-Hoo from the Department of Microbiology, Faculty of Medicine, University of Malaya, for performing the special staining for P. carinii and Mr Manivasagar for updating the records at the SLE clinic.
References DB, Petri M, Whiting-O’Keefe Q. Fatal infections in systemic lupus erythematosus: the role of opportunistic organisms. Medicine 1987; 66: 341-8. et al. Systemic lupus Lee P, Urowitz MB, Bookman AAM erythematosus: a review of 110 cases with reference to nephritis, the nervous system, infections, aseptic necrosis and prognosis. Q J Med 1977; 46: 1-32. Staples PJ, Gerding DN, Decker JL, Gordon RS. Incidence of infection in systemic lupus erythematosus. Arthritis Rheum 1974;
1. Hellmann
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17: 1-10. 4.
Ting HC, Wang F. Scabies and systemic lupus erythematosus. Int
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J Dermatol 1983; 22: 473-6. Wang F, Chua CT, Bosco J.
6. 7.
8.
Herpes zoster in patients with systemic lupus erythematosus. Singapore Med J 1983; 24: 218-20. Burke BB, Good RA. Pneumocystis carinii infection. Medicine 1973; 52: 23-51. Walzer PD, Perl DP, Krogstad DJ, Rawson PG, Schultz MG. Ann Intern Pneumocystis carinii pneumonia in the United States. Med 1974; 80: 83-93. Peters SG, Prakash UBS. Pneumocystis carinii pneumonia. Am J
Med 1987; 82: 73-8. et al. The 1982 revised criteria 9. Tan EM, Cohen AS, Fries JF for the classification of systemic lupus erythematosus. Arthritis Rheum 1982; 25: 1271-7. JC al. Laboratory aspects of SLE 10. Wang F, Simmons P, White et
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in Malaysians. I. Comparison of ESR determinations to clinical and immunological parameters. Asean J Clin Sci 1980; 1: 239-43. Grocott RG. A stain for fungi in tissue section and smears using Gomori’s methenamine silver nitrate technique. Am J Clin Pathol 1955; 25: 975-9. JL al. The usefulness of Bigby TD, Margolskee D, Curtis et induced sputum in the diagnosis of Pneumocystis carinii pneumonia in patients with the acquired immunodeficiency syndrome. Am Rev Respir Dis 1986; 133: 515-8. Frank AO. Apparent predisposition to systemic lupus erythematosus in Chinese patients in West Malaysia. Ann Rheum Dis 1980; 39: 266-9. Young LS. Pneumocystis carinii pneumonia. In: Lefant C., ed. Lung Biology. New York: Marcel Dekker, 1984: 139-220. Hughes WT. Pneumocystis carinii pneumonitis. Chest 1984; 85: 810-3. Fauci AS, Dale DC, Balow JE. Glucocorticosteroid therapy: mechanism of action and clinical considerations. Ann Intern Med 1976; 84: 304-12. Fauci AS. Mechanisms of the immunosuppressive and antiinflammatory effects of glucocorticosteroids. J Immunopharmacol 1978; 1: 1-9. Balow JE, Harley D, Fauci AS. Cyclophosphamide suppression of established cell mediated immunity: quantitative vs qualitative changes in lymphocyte populations. J Clin Invest 1975; 56: 65-71. Steinberg AD. Modern concepts of systemic lupus erythematosus. In: Cohen AS, ed. Progress in Clinical Rheumatology, Vol 1, Florida: Gmnd & Stratton, 1984: 15-7. Hoffman T. Natural killer function in systemic lupus erythematosus. Arthritis Rheum 1980; 23: 30-1. Perez H, Andron R, Goldstain I. Infection in patients with 1326-33. Arthritis Rheum 1979; 22: systemic lupus erythematosus. Nived O, Sturfelt G, Wollheim F. Systemic lupus erythematosus and infection: a controlled and prospective study including an epidemiology group. Q J Med 1985; 55: 271-87. Winston DJ, Lau WK, Gale RP, Young LS. Trimethoprimsulphamethoxazole for the treatment of Pneumocystis carinii pneumonia. Ann Intern Med 1980; 92: 762-9. Lefkowitz LB Jr. Management of Pneumocystis carinii pneumonia. New Engl J Med 1977; 296: 47 (letter). Raska K, Raskova J, Shea SM et al. T cell subsets and cellular immunity in end-stage renal disease. Am J Med 1983; 75: 734-40. Kovacs JA, Hiemenz JW, Macher AM et al. Pneumocystis carinii
pneumonia: a comparison between patients with the acquired immunodeficiency syndrome and patients with other immunodeficiencies. Ann Intern Med 1984; 100: 663-71. 27. Ballardie FW, Winearls CG, Cohen J et al. Pneumocystis carinii pneumonia in renal transplant recipients-clinical and radiographic features, diagnosis and complications of treatment. Q J Med 1985; 57: 729-47. 28. Hughes WT, Feldman S, Chaudhary SC, Ossi MJ, Cox F, Sanyal SK. Comparison of pentamidine isethionate and trimethoprimsulphamethoxazole in the treatment of Pneumocystis carinii pneumonia. J Paediatr 1978; 92: 285-91. 29. Sattler FR, Remington JS. Intravenous trimethoprimsulphamethoxazole therapy for Pneumocystis carinii pneumonia. Am J Med 1981; 70: 1215-21. 30. Reider J, Schwarz DE, Fernex M et al. Pharmacokinetics of the
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36. 37.
38.
antimicrobial combination sulphamethoxazole plus trimethoprim in patients with normal or impaired kidney function. Antibiot Chemother 1974; 18: 148-98. Reeves WH, Lahita RG. Clinical presentation of systemic lupus erythematosus. In: Lahita RG, ed. Systemic Lupus Erythematosus. New York: John Wiley & Sons, 1987: 382-385. Wang F, Looi LM. Systemic lupus erythematosus with membranous nephropathy in Malaysian patients. Q J Med 1984; 53: 209-26. Siber GR, Gorham CC, Ericson JF, Smith AL. Pharmacokinetics of intravenous trimethoprim-sulphamethoxazole in children and adults with normal and impaired renal function. Rev Infect Dis 1982; 4: 566-78. Kovacs JA, Masur H. Pneumocystis carinii pneumonia: therapy and prophylaxis. J Infect Dis 1988; 158: 254-9. Goodell B, Jacobs JB, Powell RD et al. Pneumocystis carinii: the spectrum of diffuse interstitial pneumonia in patients with neoplastic diseases. Ann Intern Med 1970; 72: 337-40. Forrest JV. Radiographic findings in Pneumocystis carinii pneumonia. Radiology 1972; 103: 539-44. Matthay RA, Schwarz MI, Petty TL et al. Pulmonary manifestations of systemic lupus erythematosus: review of twelve cases of acute lupus pneumonitis. Medicine 1974; 54: 397-409. et al. Intensity of immunoHughes WT, Feldman S, Aur RJA suppressive therapy and the incidence of Pneumocystis carinii pneumonitis. Cancer 1975; 36: 2004-9.
(Accepted 10 August 1992)
385
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Kuala
Lumpur, Malaysia
At the
University Hospital, Kuala Lumpur, Malaysia, nine patients with systemic lupus erythematosus (SLE) were treated for Pneumocystis carinii pneumonia (PCP) between January 1987 and December 1988. When they developed PCP all the patients’ SLE disease course was active and eight of them were on prednisolone. Four of these eight patients were also receiving cyclophosphamide. Patients who were on more intensive immunosuppressive
therapy were found to develop more severe PCP. All the patients except one were treated with high-dose cotrimoxazole. Four patients responded to antipneumocystis treatment and survived, while PCP was responsible for the death of the five non-survivors. Key Words: Pneumocystis carinii pneumonia SLE
Introduction Patients with systemic lupus erythematosus (SLE) are prone to opportunistic infections by bacteria, fungi, viruses and parasites’-’. The susceptibility to infection is increased when the disease is active. This may in part be due to the use of immunosuppressive therapy. Pneumocystis carinii pneumonia (PCP) is a serious and life-threatening complication of therapy associated with immune suppression 6,7. SLE patients, especially those who are receiving immunosuppressive therapy, are among those at risk of developing pCpl,7.’. This diffuse progressive pneumonia should be suspected when such patients develop unexplained respiratory symptoms and chest radiograph changes. This paper reports our experience with PCP in nine SLE patients.
Patients and methods From June 1974,
before the involvement was considered to be due Such investigations included microbiological studies, biochemical and serological tests, tissue biopsies, arterial blood gas analysis and lung function tests. The severity of the illness was judged by the number of systems involved and according to a set of criteria previously described by us &dquo;’. Patients with minor symptoms were treated symptomatically. Ill patients were initially treated with 60-80 mg oral prednisolone a day. The dose of prednisolone was then reduced gradually at monthly intervals as the activity of SLE lessened. In some patients prednisolone could be discontinued but those with residual symptoms stayed on a maintenance dose equivalent to 5 mg prednisolone a day. Patients who were toxic and very ill with multisystem involvement were given bolus intravenous methylprednisolone at 1 g daily for 3 consecutive days. This was sometimes repeated after 3-4 weeks when the patient was still very ill. Oral cyclophosphamide at 2 mg/kg/day was added when patients had not shown adequate improvement of renal involvement after 3 months. When there was exacerbation of SLE with multisystem involvement, oral prednisolone was resumed as described ant cyclophosphamide later when response was. inadequate, when persistent inflammation in the was confirmed by renal causes
patients
with SLE
were
studied pro-
spectively at the University Hospital, Kuala Lumpur, Malaysia. Patients were referred from all parts of the country when their illness
was
referred, generally ~ft~r parti~i
severe, or were selftreatment elsewhere or
when there was severe renal involvement. Only patients who fulfilled criteria for the of SLE according to the American Rheumatism Association’ were accepted into the study. Those who were clinically SLE were followed up with the SLE patients and were admitted into the SLE register when they fulfilled the criteria for the diagnosis of SLE. Patients with any target organ involvement were investigated to exclude other treatable
to SLE.
biopsy. Patients were suspected to have PCP when despite being on immunosuppressive therapy for SLE they developed inordinate dyspnoea, fever and non-productive cough with minimal chest associated with chest radiograph changes and respiratory failure that were not commensurate with the chest signs. The diagnosis of PCP
Correspondence: Liam Chong-Kin, M.B.B.S., M.R.C.P. (UK).
was
confirmed when the cysts of P. carinii
379
Downloaded from lup.sagepub.com at UNIV OF MASSACHUSETTS on April 2, 2015
were
found in pulmonary secretions by Gomori’s methenamine silver stain &dquo;. Diagnostic procedures included fibre-optic bronchoscopy with broncho-alveolar lavage (BAL) and bronchial brushing, tracheal aspirations via endotracheal tube while the patient was on mechanical ventilatory support, and induction of sputum production by inhalation oaf 3% saline. Fibre-optic bronchoscopy with the Olympus fibreoptic bronchoscope BF-10 was performed under local anaesthesia with parenteral sedation with midazolam. After inspection of the airways the tip of the bronchoscope was wedged into a subsegmental bronchus in the region of greatest radiological abnormality or in an anterior subsegment of the right middle lobe if the radiological changes were diffuse and bilateral. BAL was performed by instillation of sterile normal saline (100 ml) at room temperature in aliquots of 20 ml. Suction was then applied until at least half of the volume was collected in a secretion trap. Sheathed catheter bronchial brushings were performed with sheathed cytology brush BC-5C. The brushing material was smeared in a sinuous fashion over a 4 x 2 cm area on four glass slides, air dried and delivered without delay to the microbiologist for staining. Half of the lavage fluid was sent for staining and culture of organisms. The other half of the BAL sample was centrifuged at 3000 rpm for 5 min and the resulting deposit was spread onto several glass microscope slides and air dried. Transbronchial lung biopsy was attempted in two patients but was unsuccessful in both patients. Sputum was induced as described by Bigby ~~ ai. 12. The patient was fasted for at least 4 h before the induction. After cleaning teeth, gums and oral cavity by brushing and gargling with tap water, the patient inhaled a mist of 3 ~lo saline, generated by an ultrasonic nebulizer (Mistogen, model EN 145, Oakland, CA, USA) during tidal breathing for 10-20 min. The mask was removed, and the patient was instructed to breathe deeply three or four times keeping the mouth open, and then to cough forcefully, leading to expectoration. At least three aliquots of sputum were collected. If little sputum was produced, the induction time was extended by 5-Ifl min. Centrifugation was used to concentrate the sputum specimen to make it easier to detect the ~’. ~c~rit~~~ cysts. Tracheal secretions were obtained by suction through the endotracheal tube with a mucus extractor when patients with respiratory failure were on mechanical
ventilatory support. All preparations were stained to identify P. carinii cysts by means of Grocott’s modification of Gomori’s methenamine silver stain, the result of which was ready within several hours. All specimens were also stained with Ziehl-Neelsen stain for mycobacteria. Cultures were performed for mycobacteria and fungi. Aerobic
and anaerobic cultures for pyogenic bacteria were also performed. Facilities for culture of legionella and cytomegalovirus were not available. Blood cultures for bacteria and fungi were performed. Serological tests for legionella and cytomegalovirus were also carried out. Data regarding the clinical features, activity of SLE at the time of diagnosis of PCP, immunosuppressive therapy, chest radiograph changes, diagnostic procedures, antipneumocystis treatment and the outcome were
reviewed.
Results Since June 1974 patients with SLE have been seen either in the wards or in the clinics and followed up by one of us (FW) at the SLE clinic, initially at close intervals; as their disease condition improved, patients were seen at less frequent intervals. Patients from out of town were also followed up in the clinic. From June 1974 until December 1986, 416 patients with SLE had been seen at our hospital. Out of these, 69 patients had died and 82 had defaulted. The rest were on regular follow-up in the SLE clinic. From January 1987 to December 1988, 86 new cases of SLE were seen. Between January 1987 and December 1988, a total of 351 new and follow-up patients with SLE were seen at our hospital. Among those who needed hospitalization, some were new cases, and some were readmissions for exacerbation of SLE and for other problems not directly related to SLE. Of these 351 patients, nine developed PCP. During the same period there were 66 other cases of microbiologically confirmed F~F’, all of which occurred in patients with leukaemias who were on cytotoxic
chemotherapy. The overall racial distribution of SLE patients seen the University Hospital were Chinese 78.3%, Malay 17.2% and Indian 4.5~’~’~. The male to female ratio
at
was
1:1 ~.
All nine patients who developed PCP in this study were Chinese and all were females. The average age of these nine patients was 27 years, with a range of 14-34 years. Five patients had had SLE for several years (i.e. 2, 5, 6, 7 and 11 years, respectively) and were being treated for relapse of the disease. SLE was newly diagnosed in the other four patients ~i.~, 1, 2, 3 and 5 months, respectively). The SLE of all nine patients was active when they developed PCP. Eight patients were receiving prednisolone in doses ranging from 10 to 60 mg daily. Four of them were also on oral cyclophosphamide at 100 mg daily. One patient was not on any treatment except for some traditional Chinese medication. The clinical features of these patients at the time of diagnosis of PCP are summarized in Tables I and II, along with immunosuppressive therapy during the 1
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Table I
Clinical data
on
SLE
patients with PCP
who survived.
AaP°2: alveolar-arterial oxygen difference; ANA: antinuclear antibody titre; BAL: broncho-alveolar lavagt; BB: bronchial brushing; C3/C4: complement 3 level (normal 66-130 mg/dl) and complement 4 level (normal 20-60 rn,gld~~; CXR: chest X-ray; iv: intravenous; PCP: Pneumocystis carinii pneumonia; TS: tracheal secretions; wbc: white blood cell.
month preceding PCP, the total white cell count and lymphocyte count at the onset of serum levels oaf complement 3 and 4 at the time of diagnosis of PCP, antinuclear antibodies, serum creatinine, initial chest radiograph changes, initial alveolar-arterial oxygen difference, diagnostic procedures, co-existing infections and antipneumocystis treatment. Eight patients had symptoms of PCP for a week or less (average 4.5 days) before the diagnosis of PCP was made. Dyspnoea, fever, non-productive cough and
crepitations on lung auscultation were the most common initial and of PCP (Table 111). While the white cell counts of the patients varied when they developed PCP, eight patients had lymphopenia ~i,~, lymphocyte count less than 1.5 x l~~/l~. The differential white cell count of one patient around the time when she developed PCP was not performed. The mean lymphocyte count of patients who survived was 0.47 x 10’/l while that of the non-survivors was 0.48 x 10’/I. The serum creatinine of six patients
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Table ~~
Clinical data
on
SLE
patients who died of PCP.
alveolar-arterial oxygen difference; ANA: antinuclear antibody titre; BAL: broncho-alveolar lavage; BB: bronchial brushing; C3/C4: complement 3 level (normal 66-130 mg/dl) and complement 4 level (normal 20-W’mg/dl); CXR: chest X-ray; iv: intravenous; PCP: Pneumocystis carinii pneumonia; TS: tracheal secretion; wbc: white blood cell.
AaP02:
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Table III
Common initial symptoms and
died before intravenous administration of the drug could be commenced. Patient 7 died soon after the diagnosis of PCP was confirmed and before antipneumocystis treatment could be instituted. Pentamidine was not
signs of P. carinii
pneumonia.
available. Patients who were on cyclophosphamide had the drug discontinued upon diagnosis of PCP. However, the dose of prednisolone could not be reduced for any of the patients because of the activity of their SLE at the time PCP was diagnosed. The clinical condition of four patients improved with the treatment of PCP. Cotrimoxazole for patient 1 had to be discontinued after 13 days because of deterioration of her renal function. Treatment was given to patient 4 for only 7 days because she developed a drug rash. Her pneumonia had already improved by then and her clinical condition did not deteriorate after discontinuation of cotrimoxazole. No follow-up bronchoscopy was performed on the patients after institution of antipneumocystis treatment. PCP was the direct cause of death in the five non-survivors. Permission for autopsy was declined in all the non-surviving cases. Co-existing infections confirmed by bacteriological methods included pneumonia due to Mycobacterium tuberculosis, Klebsiella ozaenae, Pseudomonas aemginosa and Streptococcus pneumoniae. Co-existing infections occurred with the same frequency in the survivors and non-survivors. Serological titres for legionella and cytomegalovirus were not elevated in any of the patients.
(patient 2 and all the patients in Table II) was elevated when PCP was diagnosed and before treatment with ~~tri ~xazrale
was commenced. Patients 5, 6, 7, 8 and 9 (Table II), who
on the whole intensive immunosuppressive therapy, developed more extensive PCP as seen on their chest radiographs compared to patients 1, 2, 3 and 4 (Table I) who either were not on immunosuppressive therapy or were receiving less intensive immunosuppressive were on more
therapy. Initial arterial blood gas measurements were performed when the patients were either breathing room air or receiving supplemental oxygen through face masks delivering ~~-5t~~1~ oxygen. The severity of the pneumonic process was also reflected by the initial alveolar-arterial oxygen difference, which was higher for patients with more extensive radiographic changes. The diagnostic material and pulmonary secretions from all nine were obtained during life. The diagnosis of PCP in six patients was made after the detection of .F’. carinii organisms by fibre-optic bronchoscopic procedures. In another two patients P. carinii was present in tracheal secretions obtained by endotracheal tube suction when they were on ventilators for respiratory failure resulting from PCP. In the last patient, P. carinii was demonstrated in the expectorated sputum induced by inhalation of nebulized 3% saline. Eight patients were treated with oral and/or intravenous
Discussion
well-recognized pulmonary pathogen in immunocompromised hosts. PCP is a significant and life-threatening complication of therapy associated with immune suppression’,’. Among patients at risk are those with collagen vascular disease, especially if they are receiving immunosuppressive therapy 1,7,8. Impaired cellular immunity appears to be a major risk factor 14, 15. T cells are thought to release lymphokines, which activate alveolar macrophages and/or recruit and activate
P. carinii is
trimethoprim-sulphamethoxazole (cotrimoxazole).
Patients who were able to tolerate oral therapy were given trimethoprim (20mg/kg/day) and sulphamethoxazole (100 mg/kg/day) in four equal doses. Patients who had severe PCP received intravenous trimethoprim (15 mg/ kg/day) and sulphamethoxazole (75 mg/kg/day) in four equal doses. The doses were adjusted when renal function was impaired. Two patients (patients and 2) were given oral cotrimoxazole the treatment. because they were not ill. Cotrimoxazole was initially given intravenously to patients 3 and 4 but was subsequently administered orally once their clinical conditions had improved. Only patient 5 received cotrimoxazole intravenously for the whole treatment period of 14 days. For patients 6 and 9 oral cotrimoxazole was replaced by the intravenous form when their clinical status deteriorated. Patient 8 was on oral cotrimoxazole when her condition took a turn for the worse and she
a
monocytes to kill pneumocystis. Cell-mediated immunity is suppressed by high-dose corticosteroids 16,!7 and
cyclophosphamide&dquo;.
SLE itself is associated with
a
rang of T-cell defects that may be primary or secondary to anti-’~-~~il antibodies 19. In addition, deficient natural killer (NK) cell activity has been reported in patients with active lupus20. This probably explains why one of our patients who was not on any known immunosuppressive therapy and one who was on only 1 t~ m,~ prednisolone daily developed PCP. However, the activity of SLE has been found to be a risk factor for infection in some but not all studies 1,21,22. It is not surprising that our patients on more intensive 383
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immunosuppressive therapy developed more severe PCP. Intensive immunosuppressive therapy seems to be a poor prognostic factor, as this was associated with higher mortality. However, the difference in the degree of immunosuppression between the survivors and nonsurvivors was not reflected by the mean lymphocyte counts of the two groups of patients. This could be due to the small number of patients in this study. Hellmann and co-workers’ have found a strong correlation between immunosuppressive therapy and death from infections in patients with SLE. Therefore, when patients with SLE develop PCP, the question arises as to whether immunosuppressive therapy should be reduced or discontinued with possible exacerbation of SLE activity. Some authors 23, 24 recommend tapering of corticosteroids and other immunosuppressive therapy as much as the underlying disease allows to enable the host to develop an immunological response to the infection. It is not always possible to do this, especially when the patient is suffering from active SLE with multisystem involvement at the time of diagnosis of P~P.. Patients with renal insufficiency are known to have impaired immune response&dquo;. This may enhance the susceptibility to PCP in our SLE patients and could have accounted for the higher fatality among our SLE patients who had impaired renal function. The clinical manifestations of PCP in our patients were the same as described elsewhere~, with dyspnoea, fever and non-productive cough as the most frequent initial symptoms. All except one of our patients with SLE had symptoms of PCP for a week or less (average 4.5 days) before the diagnosis was made. Other investigators 26 have found that the duration of prodromal symptoms of PCP in patients with diseases requiring immunosuppressive therapy is shorter compared to that in patients with the acquired immunodeficiency syndrome (AIDS). Patients with AIDS had symptoms for a mean of 28 days before diagnosis, while patients with other immunosuppressive diseases had symptoms for a mean of 5 days. Untreated, pneumocystis pneumonia almost always runs a progressive and fatal courses. With appropriate chemotherapy ~(3-~~~~ of patients recover from this infection 15. High-dose cotrimoxazole has been the initial treatment of choice for PCP since 1978 when Hughes and co-workers 28 found it to be equally effective as the more toxic pentamidine. Intravenous treatment is recommended for the severely ill patient 29. A normogram is available to make dose adjustments in patients with impairment of renal function&dquo;. Pentamidine is an alternative drug for patients who develop adverse reactions to cotrimoxazole. Unfortunately, pentamidine was not locally available for use in our patients. All our patients were suffering from active SLE when they developed PCP. As many patients with active SLE *
also suffer from lupus nephritis with impaired renal function 31. 32, it is essential to confirm the diagnosis of PCP before initiation of therapy that may further worsen the renal function 33, 34. Although P, carinii is the most common cause of diffuse progressive pneumonia in the immunosuppressed patient&dquo; it must be differentiated from lupus pneumonitis, pulmonary oedema, occult intrapulmonary haemorrhage and other pulmonary infections 36, 37. Cytomegalovirus is a commonly identified co-existing infection with PCP and the frequency of dual infections with P. carinii and cytomegalovirus has been reported to be between 10 and 71 % &dquo;. Co-existing bacteria and other fungal infections may also be present. This underscores the need for thorough microbiological studies to determine whether any other treatable infection co-exists with PCP. The failure to make an early diagnosis of an opportunistic infection occurs when the infection simulates active SLE and when the possibility of an opportunistic infection is not thoroughly investigated 4. If any diagnostic procedure is contemplated in a SLE patient with pneumonitis it should be done early, preferably before the administration of antibiotic therapy, to ensure maximum
diagnostic yield.
Acknowledgements The authors would like to thank Associate Professor T.S. Soo-Hoo from the Department of Microbiology, Faculty of Medicine, University of Malaya, for performing the special staining for P. carinii and Mr Manivasagar for updating the records at the SLE clinic.
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(Accepted 10 August 1992)
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