Serial Pulmonary Function Tests in the Diagnosis of P. Carinii Pneumonia
Copyright ©ERS Joumais Ltd 1993 Eur Aespir J, 1993, 6, 823-827 European Respiratory Joumal Printed in UK • all rights reserved ISSN 0903 · 1936
Serial pulmonary function tests in the diagnosis of P. carinii pneumonia
D.M. Mitchell, J. Fleming, J.R.W. Harris, R.J. Shaw
Serial pulnwnary function tests in the diagnosis of P. carinii pneumonia. D. M. Mitche/1, Chest & Allergy Clinic, St Mary's Hospi· J. Fleming, J.R. W. Harris, R.J. Shaw. ©ERS Journals Ltd 1993. tal, London, UK. ABSTRACT: The predictive value of serial versus isolated measurements of trans fer factor for carbon monoxide (TLco) in the diagnosis of pneumocystis carinii pneu monia (PCP) in a cohort of 474 IDV-1 seropositive patients, with all stages of IDV Correspondence: D.M. Mitchell Chest & Allergy Clinic disease, was evaluated. St Mary's Hospital Two groups of patients were studied, one group with serial lung function meas Praed Street urements (Group 1) and another with only a single set of measurements (Group London W2 INY, UK 2). During the study period 118 patients performing serial tests developed a respi ratory illness of which 58 were performing monthly and 60 three monthly meas urements of lung function (Group 1). Keywords: Human immunodeficiency In 36 patients from Group 1, where PCP was diagnosed, monthly lung function virus tests showed a decrease in TLCo from 68% (±3.2) (SEM), (8 weeks prior to illness), P. carinii pneumonia to 44% (±2.5) predicted normal at presentation, whereas in 22 patients who did pulmonary function not have PCP, Ttco fell from 71% (±4.5) to 57% (±3.1). TLCo was thus reduced to lower values in these with PCP than in those without PCP (p
Of the pulmonary complications of human immunode transfer factor (Tu:o) and vital capacity (VC) have been ficiency virus (HIV) infection, Pneumocystis carinii shown to occur in PCP [7- 9]. Documentation of an iso pneumonia (PCP) remains the most common major lated reduction in Ttco lacks specificity as a diagnostic opportunistic infection in Europe and the USA, despite tool for PCP, as in previous studies [ lO] we observed a re the widespread use of effective prophylaxis [1]. PCP duction in Ttco in patients with a wide range of HIV -re causes diagnostic difficulties because the symptoms are lated lung disease. In a subsequent study, utilizing serial nonspecific [2-4], and physical examination is usually measuremenls of pulmonary function, we found that although non-contributory. A chest radiograph in PCP may be often reduced, the value of the Ttco was essentially stable normal or may show atypical features, and radio in patients who did not experience a clinical deterioration graphic features of PCP may be seen in other acquired [11]. Conversely, we observed that there was a decline in immune deficiency syndrome (AIDS) related pulmonary Ttco in many patients during a clinical deterioration. infections or tumours. A definite diagnosis of PCP, there In this study we first looked at the diagnostic value of fore, requires examination of induced sputum, broncho a single measurement of Ttco at the time of presenta alveolar lavage, or transbronchial biopsies [5]. Much recent tion with respiratory disease; and, secondly, we asked effort has been devoted to the application of indirect teste;, whether the magnitude of the decline of TLco, as identi including measurement of pulmonary function, in the evalu fied by serial measurements of pulmonary function, was ation of patients with HIV infection, who present with res able to discriminate PCP from other acute respiratory piratory symptoms [6]. Low values for carbon monoxide illnesses in mv-infected patients. 824 D.M. MITCHELL ET AL.
Methods used for spirometry, to avoid the risk of inhaling patho gens from the spirometer. A Pall Ultipor breathing sys These studies were performed on a cohort of male ho tem filter {Pall Biomedical, Havant, Portsmouth) was mosexual or bisexual IDV seropositive patients. Consecu placed distal to the mouthpiece during the CO transfer tive patients who attended the sexually-transmitted disease test. The increased tidal volume of 150 m! due to the clinic were enrolled. It is policy to include pulmonary presence of the filter was incorporated in the calculation. function testing in the initial work-up of these patients. Plastic mouthpieces and noseclips were sterilized in 2% The criteria for inclusion in the study were: l) positive glutaraldehyde for l h between patients, and the remain IDV serology; 2) no history of intravenous drug abuse; der of the apparatus dismantled and sterilized weekly for and 3) informed consent. Exclusion criteria were: l) res >3 h in 2% glutaraldehyde. piratory failure; and 2) refusal of the patient to partici Values were compared with those predicted for age, sex pate. and height [14], and statistical comparisons were made The patients were classified according to clinical using the Mann-Whitney U test. This study was ap status: 1) 126 asymptomatic HIV seropositive (HIV+) proved by the hospital Ethics Committee. (CDC group ll) [12]; 2) 95 with persistent generalized lymphadenopathy (PGL) (CDC group ffi); 3) 92 with AIDS-related complex (ARC) (CDC group N, subgroups Results A, B, C2, E); 4) 35 with non-pulmonary Kaposi's sar Of the 118 patients who had an acute respiratory coma (KS) (mainly skin Kaposi's sarcoma) (CDC group ill ness and were performing serial lung function tests IV, subgroup D); 5) 19 with non-pulmonary, non-KS patients {Group 1), PCP was confirmed in 65 patients. AIDS (i.e. opportunistic infection involving other organs) The other 53 patients with acute non-PCP respiratory (CDC group N, subgroup Cl); and 6) 107 AIDS patients disease were initially thought to have PCP on the basis with pulmonary complications (pulm AIDS), 78 with of symptoms and chest radiograph appearance, but fol acute PCP (CDC group N, subgroup Cl), and 42 of lowing bronchoalveolar lavage these patients were found these patients 3 months following recovery from PCP not to have PCP but pyogenic bacterial chest infection, (post-PCP), 11 with lung mycobacterial infection (lung mycobacterial infection, or no established aetiological myco), 11 with lung Kaposi's sarcoma (lung KS), and 7 diagnosis. None of these patients required or received AIDS patients with pulmonary pyogenic bacterial infec treatment for PCP. Data from respiratory function tests tion. performed at monthly intervals were available from 36 Lung function testing was performed at 1 or 3 monthly patients with PCP and from 22 patients with acute non intervals, as part of routine out-patient follow-up. Com PCP respiratory disease. Data from tests performe9 at 3 pliance was high, as many patients were attending on a monthly intervals were available in the remainder. In the regular basis for monitoring of zidovudine therapy, or larger group of 474 patients with all categories of HIV were involved in other studies relating to their HIV disease, comparison was made between the results of an infection. isolated measurement of lung function and the clinical Patients seropositive for HIV with an abnormal chest stage of HIV-related disease at that time. radiograph, or TLco of <70% predicted, or prominent respiratory symptoms (i.e. persistent cough, or moderate to severe exertion, or dyspnoea) underwent fibreoptic Serial measurement of TLco (Group 1) bronchoscopy with bronchoalveolar lavage, with or with out transbronchial biopsy [13]. All patients had the fol When the TLco values 8 weeks prior to the respiratory lowing lung function tests: forced expiratory volume in illness were compared, the TLco was found to have been
one second (FEV1), peak expiratory flow (PEF), forced reduced both in those with PCP and in those with acute vital capacity (FVC), alveolar volume (V A), and diffus non-PCP respiratory disease. The TLco in those with PCP ing capacity of the lung for CO (TLco). The diffusion was 68±3.2% predicted (mean±sEM), and in those with coefficient (Kco) was derived from TLco and VA. Meas acute non-PCP respiratory disease was 71±4.5% predicted. urements were made using a dry bellows spirometer, and In patients who developed PCP, there was a small fall the single breath helium dilution method (PK Morgan in TLco by I month prior to the diagnosis of PCP, when transfer test model C machine, PK Morgan, Gillingharn, compared to TLco measurements 8 weeks prior to the res Kent, UK). Corrections for temperature and haemoglobin piratory illness (fig. 1). During the 4 weeks leading up [14] were included when calculating values of TLco. All to the diagnosis of PCP, there was a further more marked measurements were made after a period of rest. Tests decline in TLco. One month after the diagnosis of PCP were repeated at approximately 3 monthly intervals, de and the initiation of therapy, the TLco values were simi pending on stage of disease and clinical indications. If a lar to those 1 month prior to diagnosis. There was a fur decline in TLco was noted in consecutive tests, then lung ther slow improvement in TLco when measurements were function measurements were repeated 4 weeks later. taken 8 weeks after PCP, the TLco values being only To reduce the risk of cross-infection between patients, slightly below those recorded 2 months prior to PCP. modifications were made to the equipment. Lung func The pattern of changes in TLco in patients with acute tion testing apparatus designated for HIV seropositive pa non-PCP respiratory disease was similar, but the magni tients was used throughout. One way valve safety tude of the changes was less marked. Thus, the reduc mouthpieces (Vitalograph Ltd, Buckingham, UK) were tion of TLco during the acute illness was from 71 to 57%, SERIAL PULMONARY FUNCTION IN lDV 825 when compared to 68 to 44% for the PCP group. The 7p% nadir values of Tr..co were significantly lower in the PCP 35 . patients than in the acute non-PCP respiratory disease pa 30 tients (p<0.05). 25 80 20 15 70 10 5 0 -1--,....-,...... ,.--..-.,...... 60 25 20 50 15 10 40 5 0 +---~--~~--~--~--~--~ -8 -4 0 4 8 12 o+--.~....-. 100 20 ARC 15 90 10 5 0 -1--..--.-_,...-.
~ j ~. • . IIP.D.o ~ skin Ks 70 ~ j .• .lit=l,D.., Non-lung AIDS 60 20 0 +----r----~--~--~----~---, -8 -4 0 4 8 12 15 10 Acute PCP 100 5 0 90 10 Post-PCP 5
0 80 0 -1--...... --lfll. .... ~ Lung KS 70 ~ +-1--..--.---.- ~...... 1 ....1-,l.n,_..,..--.--.-.-- ...... 1' 60 Bronchoscopy ~ ]+--.J.--..-..•-....--. .,--+___,..,Q~,D...... -.- .....L- u.---.ng myco ' 0 4---~----~---r--~~--~--~ -8 -4 0 4 8 12 ~ +1~~~-~•~.-~~~.~.-~,m~.~.-Lu~~g~~y~ Weeks 0 20 40 60 80 100 120 140 PCP n = 33 34 36 34 34 TLCO % predicted Non PCPn= 20 21 22 22 19 Fig. 2. - Frequency distribution of Ttco (as percentages of predicted normal values) in the different categories of HJV -related disease, show Fig. I. - Serial measurements of Tu::o, FVC and Kco in HIV sero ing numbers of patients with values of <70% and of ;:::70% (deline positive patients with PCP (e). and with acute respiratory disease other ated by dolled line). HIV: human lmmunodeliciency virus; PGL: than PCP (0 ). 0 week: onset respiratory illness. **: p The changes in Ttco were also reflected in changes in distinguish between patients with PCP and patients with the FVC. There was a marked decline in FVC in the 1 other acute respiratory illness. This study confirms pre month prior to the diagnosis of PCP, which was less vious findings [10] that a low TLco is a sensitive index marked in patients found to have non-PCP respiratory dis for pulmonary disease in AIDS, in that it was reduced ease. Similarly, the nadir FVC value was significantly to below 70% of predicted normal in 92% of patients lower in the PCP group, when compared with the acute with PCP. However, a low value for Tt.co was not spe non-PCP respiratory disease group (p<0.05). There was cific for PCP, with a specificity of 7 1% when compared a slight reduction in Kco, which was similar in both to the cohort as a whole, and of 62% when compared to patient groups. those groups of patients with respiratory complications of HIV infections other than PCP. On the other hand, in view of the rugh negative predictive value (98%) of a low Relationship between magnitude of decline in Tu:o and 1Lco measurement, a single measurement of Tlco can be presence of PCP of clinical and diagnostic value since, if the TLco is nor mal, PCP is virtually excluded. In the study Group I of 118 patients, the magnitude Low values for Ttco could not be attributed to intra of the decline in Tlco over a 3 month period was not venous drug abuse, as none of the patients in this study related to the underlying diagnosis. The 1Lco declined by were intravenous drug abusers [15]. Serial measurements a mean of 14.7±1.7% in those with PCP, and 10.5±1.3% of lung function in HIV seropositive patients, initiated in those with acute non-PCP respiratory disease. The me prior to the onset of an acute respiratory illness, have the dian decline in the two groups was 11 .0 and 9.0%, re theoretical advantage that changes in 1Lco can be related spectively. Although the greatest declines occurred in to the individual's own baseline value, although in prac those with PCP, there was considerable overlap between tice it may be difficult to obtain measurements prior the groups. A cut-<>ff value of decline in Ttco of 5% pre to respiratory illness. The present study found that there dicted was taken. When used as a diagnostic test for PCP, was a decrease from baseline in 1Lco in patients with this bad a sensitivity and specificity of 75 and 28%, re PCP and acute non-PCP respiratory disease. This decline, spectively. This test had a positive predictive value of at least in the PCP patients, commenced prior to 1 month 56%, and a negative predictive value of 48%. before the diagnosis was made. However, the greater part of the decline in Ttco in both groups occurred in the 4 weeks prior to clinical presentation and diagnosis by bron Isolated measurement of TLCo (Group Z) choscopy. When the groups were considered as a whole, the PCP patients had Tt..co values lower than the patients Seventy eight of the 474 patients in the overall study had with acute non-PCP respiratory disease. When each in acute PCP either at presentation or during the follow-up pe dividual was considered, there was considerable overlap riod. During acute PCP in this group, the TLco was 49±1.8% between the magnitude of the decline in TLco between of predicted normal, the FVC was 74±2.6%, and the Kco the two patient groups. Thus, if a further decrease in Ttco 72±2.3% Only 6 out of 78 patients with PCP had a TLco of 5%, when compared to the individual's initial value, of >70% predicted, whereas 52 and 38 patients had values was used as a diagnostic test for PCP, it had a sensitiv for FVC and Kco of >70%. Although the TLco was the most ity of 75% and a specificity of 28%. It would be diffi sensitive index for the presence of PCP, a reduced TLco cult in practice to offer serial lung function testing to all was not specific for PCP, as marked reductions in TLco HIV positive patients, and this study suggests that such were also seen in other categories of pulmonary disease a policy would not help identify those with PCP. (fig. 2). When a Ttco value of <70% predicted was used The exact pathogenic mechanism underlying the decline to diagnose PCP, the sensitivity of the test was 92%. The in 1Lco AND HIV-infected patient~ is unclear. We have specificity of the test, when compared to all other patient not been able to document a consistent defect in the lungs groups, (i.e., the cohor of 474 patients was 71%. The of asymptomatic HIV seropositive patients with reduced specificity was further reduced to 62%, when patients with Ttco using exercise tests, diethylenetriarnine penta-acetic PCP were compared only with the patients from the cohort acid (DTPA) clearance, or high resolution computed to with other respiratory complications of infection, namely mv mography (Cl) scanning [16]. pulmonary Kaposi's sarcoma, mycobacterial infection, and In a previous study [ll], the 1Lco remained essentially pyogenic bacterial infection. When compared to the co unchanged in the absence of a clinical deterioration, and hort as a whole the positive predictive value was 34%, we argued that HIV infection alone did not result in pro and the negative predictive value was 98%. The negative gressive lung damage. The present study extends these predictive value was lower at 33%, when acute PCP was observations by finding that both PCP and acute non-PCP compared to pulmonary Kaposi's sarcoma, mycobacterial respiratory disease caused an acute deterioration in lung infection, and pyogenic bacterial infection. function over a few weeks. The data suggest that a de cline in 1Lco exceeding 5% may indicate an acute res Discussion piratory illness, but cannot identify those with acute PCP. In this study we have assessed the ability of serial lung Acknowudgements: The authors would like to thank function tests to identify HIV seropositive patients with S. Crossan for her seccetarial work in preparing the respiratory complications, and the ability of these tests to manuscript. SERIAL PULMONARY FUNcnON IN HIV 827 References the acquired immunodeficiency syndrome. Chest 1985; 87: 104-112. 1. Chain SM, Mintz S, Chan CK. - Changes in hospital 9. 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