Bronchiectasis in HIV Disease

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1 Quarterly Journal of Medicine, New Series 85, No , pp , November-December 1992 Bronchiectasis in HIV Disease AH HOLMES, B TROTMAN-DICKENSON*, A EDWARDSf, TEA PETO and GA LUZZI From the Infectious Diseases Unit, and "Department of Radiology, Churchill Hospital, Oxford 0X3 7LJ and ^Genitourinary Medicine Department, Radcliffe Infirmary, Oxford 0X2 6HE Accepted 7 September 1992 SUMMARY An increased frequency of bacterial pneumonia occurs in HIV-infected individuals: however the development of bronchiectasis is not well recognized. We describe seven patients with HIV infection who developed chronic symptomatic lung disease, six with troublesome recurrent infective exacerbations. Bronchiectasis was demonstrated by computed tomography in five patients, and bronchial wall thickening was shown in a further two patients. The characteristics of the patients are described, and possible aetiological factors are discussed. As measures become available which prolong the later stages of HIV disease, bronchiectasis may become an increasing problem in this patient population. Early recognition and appropriate management may significantly alter morbidity in advanced HIV disease. INTRODUCTION Bronchiectasis, the irreversible dilatation of the bronchial tree, is a well-recognized complication of severe or recurrent chest infection, and chronic bronchial wall thickening is a feature [1]. Recognized predispositions include immunoglobulin deficiency, cystic fibrosis, ciliary dysfunction, and bronchial obstruction. An increased frequency of bacterial pneumonia has been described in HIV-infected patients; however the development of bronchiectasis has only rarely been documented [2-4]. We describe seven HIV-infected patients in whom bronchiectasis or bronchial wall thickening was demonstrated. SUBJECTS AND METHODS HIV-1 infected patients followed in Oxford (Infectious Diseases Unit, Churchill Hospital; Genitourinary Medicine Department, Radcliffe Infirmary; and Oxford Haemophilia Centre) comprise approximately 120 haemophilia patients, and 100 patients in whom the infection was acquired sexually or in relation to intravenous drug use. The haemophilia group acquired their infection from contaminated factor VIII between 1979 and Address correspondence to: Dr Luzzi, University of Oxford, Nuffield Department of Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU Oxford University Press 1992

876 AH Holmes and others Between 1989 and June, 1992, seven patients presented with symptomatic chronic lung disease. Their case records and chest radiographs were reviewed.

2 876 AH Holmes and others Between 1989 and June, 1992, seven patients presented with symptomatic chronic lung disease. Their case records and chest radiographs were reviewed. High resolution computed tomography of the chest in series of 1 mm thick sections was performed in six patients at times when there was no acute infection. The chest radiographs and CT images were independently reviewed by two radiologists. None of the patients had a history of lung disease before acquiring HIV infection: no patient had previously experienced chronic cough, sputum production, haemoptysis, or prolonged episodes of winter bronchitis needing antibiotics for resolution. The following case descriptions illustrate the clinical presentations and findings. Case Descriptions A 23-year-old haemophiliac {Patient 1) was admitted with acute left lower lobe pneumonia, and had a history of non-productive cough for 3 months. Profuse Streptococcus pneumoniae was grown from induced sputum. He was a smoker of 20 cigarettes daily, and was taking low-dose cotrimoxazole as prophylaxis against Pneumocystis carinii pneumonia. Following treatment of the acute infection with amoxycillin his cough persisted, associated with bilateral basal lung crackles. He now has a chronic productive cough with regular infective exacerbations requiring oral or intravenous antibiotics, and has derived symptomatic benefit from daily home physiotherapy and postural drainage. An 18-year-old haemophiliac (Patient I) presented with a worsening chronic productive cough. He had had Pneumocystis carinii pneumonia 18 months previously, and was taking zidovudine and low-dose cotrimoxazole. Over subsequent months he experienced multiple infective exacerbations requiring antibiotics, and his cough became associated with persistent coarse bilateral basal crackles. During one such exacerbation, profuse Haemophilus influenzae was isolated following bronchoalveolar lavage, and treatment with high-dose amoxycillin (3 g daily) produced a good clinical response. On maintenance high-dose amoxycillin and regular physiotherapy with postural drainage at home he has experienced no further exacerbations. A 22-year-old haemophiliac (Patient 3) presented with fever and cough. He had had Pneumocystis carinii pneumonia 15 months previously, and was taking zidovudine and lowdose cotrimoxazole. Acid fast bacilli were seen in induced sputum, and Mycobacterium kansasii grown on culture. He received rifampicin, isoniazid, ethambutol and pyrazinamide with no significant improvement in symptoms over 2 months: his cough worsened and he developed persistent bilateral basal crackles. On the basis of in vitro sensitivities, isoniazid and pyrazinamide were replaced by ciprofloxacin and amikacin, with resolution of fever and symptomatic improvement. Four months later he developed pleuritic chest pain, wheeze, productive cough and sinusitis; S. pneumoniae was isolated from nasal discharge. He receives regular chest physiotherapy. A 19-year-old male with von Willebrand's disease (Patient 4), a cigarette smoker, presented with right lower lobe pneumonia. For 18 months he had been troubled by intermittent sinusitis. Four months previously he had had Pneumocystis carinii pneumonia, and was taking zidovudine. A heavy growth of Pseudomonas aeruginosa was isolated from sputum. Bronchoscopy demonstrated noendobronchial lesion, and bronchoalveolar lavage yielded only P. aeruginosa. He showed a dramatic response to intravenous ceftazidime, several previous antibiotic regimens having made little impact. He received regular chest physiotherapy and learned to perform postural drainage at home. A further exacerbation responded to ciprofloxacin. Four months later he was readmitted with fever and a cavitating right upper lobe lesion. He refused further bronchoscopy, and died despite treatment with

3 Bronchiectasis in HIV Disease 877 broad-spectrum antibiotics and amphotericin. Permission was not granted for post-mortem examination. A 35-year-old male injecting drug user {Patient 5) presented with fever and a productive cough. He had no history of opportunistic infection but had been losing weight for 2 months. He smoked 20 cigarettes daily. Chest radiographs showed right lower lobe consolidation, and sputum produced a heavy growth of H. influenzae; P. carinii was not detected. He responded well to ampicillin, and following recovery coarse basal crackles, predominantly right sided, persisted at the lung bases. He experienced intermittent exacerbations of cough associated with wheeze, pleuritic pain and pleural rub. Profuse H. influenzae was grown from sputum during several exacerbations, which responded well to early self-treatment with amoxycillin. Nine months later he died following an acute exacerbation during which H. influenzae was isolated from blood and sputum. CT of the chest and post-mortem examination were not performed. A 43-year-old homosexual man (Patient 6) presented with a history of recurrent chest infection, occurring every 3 months or so for over 1 year. For 6 weeks he had experienced cough productive of green sputum, and had lost weight. He was receiving zidovudine, and monthly nebulized pentamidine as prophylaxis against Pneumocystis carinii pneumonia. On examination he was apyrexial and lung crackles were audible at both bases. Branhamella catarrhalis was isolated from sputum. A 51 -year-old homosexual man (Patient 7) developed chronic productive cough, worse in the mornings, which persisted over an 18-month period. He had experienced several infective exacerbations requiring oral or intravenous antibiotics. He had presented 4 years previously with Pneumocystis carinii pneumonia, confirmed on bronchoalveolar lavage, and had received zidovudine and later dideoxyinosine. He subsequently developed chronic sinusitis with opacification of the maxillary antra on radiography, and cytomegalovirus retinitis, for which he received gancyclovir. He has persistent crackles over the left lower lobe, and sputum culture suggests chronic colonization with P. aeruginosa. He is managed with regular physiotherapy and postural drainage, and antimicrobials, including anti-pseudomonal agents, for infective exacerbations. RESULTS The patient characteristics are summarized in Table 1. The major risk groups for HIV infection were represented among the seven subjects: four had received contaminated factor TABLE 1. Individual characteristics of HIV-infectedpatients with bronchiectasis Patient no. Age/sex Risk for HIV Years HIV ve CD4 cells (x 10 9 /L) Previous opportunistic infections Other problems /M 18/M 22/M 19/M 35/M 43/M 51/M Haemophilia Haemophilia Haemophilia von Willebrand's disease IDU Homosexual Homosexual > Cryptosporidiosis, herpes zoster. oesophageal candidiasis PCP, herpes zoster PCP, cryoptosporidiosis, oesophageal candidiasis PCP, herpes zoster, oesophageal candidiasis None Oral candidiasis PCP, CMV retinitis Severe, recurrent oral aphthous ulcers Recurrent sinusitis Recurrent sinusitis Dementia, cachexia Chronic sinusitis PCP=/ >. carinii pneumonia, IDU = injecting drug user; CMV = cytomegalovirus.

4 00 -J oo TABLE 2. Features of bronchiectasis in HIV-infected patients Patient no Chronic cough Chronic sputum Persistent crackles Recurrent chest infs. Microbiology 5. pneumoniae (sputum) H. influenzae (BAL) S. pneumoniae (nasal discharge) M. kansasii (sputum/blood) P. aeruginosa (sputum, BAL, nasal discharge) H. influenzae (sputum/blood) B. catarrhalis (sputum) P. aeruginosa (sputum) Chest radiographs Basal linear markings Basal linear markings Normal Transient right basal infiltrates Basal linear markings Basal linear markings Left basal scarring HRCT Bilateral basal bronchiectasis Bilateral basal bronchiectasis Bilateral basal bronchial wall thickening RML and RLL bronchiectasis ND Bilateral basal bronchiectasis RML bronchiectasis HRCT, high resolution computed tomography; BAL, bronchoalveolar lavage; RML, right middle lobe; RLL, right lower lobe; ND, not done. 3" 2 Q 3 a. o 2J~ "5 ^i to

5 Bronchiectasis in HIV Disease 879 FIG. 1. Chest radiograph of an 18-year-old HIV-positive haemophiliac {Patient 2). Ill-defined linear opacities and 'tramlining' (arrow) in the left lower lobe medially represent bronchial wall thickening. VIII, two were homosexual and one was an injecting drug user. All subjects were male, the mean age was 31 years (range 18-51), and three were cigarette smokers. The clinical features are summarized in Table 2. All seven patients presented with chronic cough, five with chronic sputum production, and six with recurrent chest infection. No patient was clubbed or cyanosed on examination; persisted lung crackles were audible in all seven patients. In four patients the chest radiograph showed abnormally prominent and crowded linear markings indicative of bronchial wall thickening (Fig. 1). Normal appearances on chest radiographs had previously been documented for two of these patients {Patients 2 and 5) and two others {Patients 4 and 7). In the six patients in whom high resolution CT was performed, bronchiectasis was apparent in five and bronchial wall thickening alone was demonstrated in a further patient. The cross-sectional diameter of dilated bronchi was greater than that of adjacent pulmonary arterial vessels, which should normally be of equivalent size ('signet ring' sign, Fig. 2). Normal CT apperances had previously been documented for two patients: 7 months before for Patient 3, and 8 months before for Patient 7. For most subjects, only an estimate of duration of HIV positivity was possible: for the five subjects with definite bronchiectasis, the mean period of HIV positivity before presentation with chronic lung symptoms was 7.2 years (range 5-10). The CD4 lymphocyte counts at presentation were very low in all cases, with a mean of 0.02 x 10 9 /l overall (range 0-0.1), and in those with bronchiectasis ( ). The mean total peripheral white cell count at presentation was 4.0 x I0 9 /l ( ), mean neutrophil count 2.7 x 10 9 /l ( ) and mean total lymphocyte count 0.8 x 10 9 /l ( ). Two patients had neutrophil counts persistently below l.ox 10 9 /l: Patient 1 (0.8 x 10 9 /l) and Patient 5 (0.9 x 10 9 /l). Four patients had had previous Pneumocystis carinii pneumonia; for these patients the mean interval between this pneumonia and presentation with chronic lung symptoms was 21 months (range 4-48).

880 AH Holmes and others FlCi. 2. Thoracic high resolution CT of a 51-year-old HIV-positive homosexual man {Patient 7), showing right middle lobe bronchiectasis.

6 880 AH Holmes and others FlCi. 2. Thoracic high resolution CT of a 51-year-old HIV-positive homosexual man {Patient 7), showing right middle lobe bronchiectasis. The dilated bronchus (arrow) is seen lying adjacent to an accompanying pulmonary artery (arrowhead): the 'signet ring' sign. DISCUSSION HIV-infected individuals are predisposed to bacterial lung infection: among HIV-positive intravenous drug users, there is almost a five-fold increase in the incidence of bacterial pneumonia compared with seronegative controls [2, 3]. However, only one report of bronchiectasis associated with HIV infection was found in a literature survey, and this was related to an endobronchial lesion [4]. Recently, McCloud and Naidich commented on an increased incidence of bronchiectasis following bacterial pneumonia in AIDS patients, but data were not provided [5]. The principal clinical features in our patients were chronic cough, often productive, associated with a tendency to infective exacerbations; chronic focal lung crackles on examination; and persistent changes on chest radiographs and lung CT scans indicative of bronchiectasis or bronchial wall thickening. High resolution CT imaging has largely replaced the more invasive bronchography as a sensitive method to identify and assess the severity of bronchiectasis [6, 7]. Recurrent bacterial lung infection may be the most important aetiological factor in the development of bronchiectasis and the preceding stages of lung damage in HIV-infected patients; however, multiple factors may contribute. Defects in B-lymphocyte function may underlie the increased susceptibility to bacterial lung infection in HIV disease [8]. Recurrent or chronic sinusitis, which occurs commonly in HIV disease, was present in three patients. The possibility of impaired respiratory secretory immunity or reduced ciliary function, which may predispose to sinusitis and bronchiectasis, needs to be studied further in HIV infection. Whether HIV may damage lung directly and contribute to the tendency to develop chronic lung disease also needs to be examined. Pneumocystis carinii pneumonia, which four of the seven patients had previously

Bronchiectasis in HIV Disease 881 experienced, has been shown to cause bronchial wall thickening [9], and may have contributed to the later development of bronchiectasis.

7 Bronchiectasis in HIV Disease 881 experienced, has been shown to cause bronchial wall thickening [9], and may have contributed to the later development of bronchiectasis. However, detailed studies on its long-term effects are lacking. In HIV-infected injecting drug users (without AIDS) in New York [3], the increased incidence of cases of pneumonia could not be accounted for by cigarette smoking, a regular habit of three patients in our series. Intravenous drug use, relevant to one of our patients, is however associated with increased risk of bacterial infections including pneumonia [3]. Early recognition of bronchiectasis and its associated features may be important in management. Standby courses of antibiotics or in severe cases continuous antibiotic treatment, as may be indicated in bronchiectasis of other cause, may be beneficial. Chronic infection with P. aeruginosa may be a complication of bronchiectasis [10], and two of our patients illustrate that antibiotic regimens may need to take this into account. Early involvement of the physiotherapist in the management of HIV patients with chronic lung symptoms, and the education of the patient and family in postural drainage at home may be important additional strategies. Various approaches to prevent bacterial infection may reduce the risk of developing bronchiectasis. The use of pneumococcal and H. influenzae B vaccines [11, 12] and pooled immunoglobulin [13] are being evaluated in the prevention of bacterial pneumonias in HIVinfected patients. This small retrospective survey indicates that bronchiectasis and its associated features may occur in the context of HIV disease with significant frequency. All our patients were at a late stage in the course of HIV infection, as reflected by very low CD4 lymphocyte counts and a tendency to develop opportunistic infections. The major risks groups for HIV infection (homosexuals, haemophiliacs and injecting drug users) were represented in this series. However the precise incidence of this complication, its distribution across the various HIV risk groups, its natural history, and the interplay of the multiple factors which may be involved in the pathogenesis need to be examined in a large prospective study. As the life expectancy of HIV-infected individuals increases with improvements in the prevention and treatment of opportunistic infections and the use of antiretroviral agents, the importance of recurrent pulmonary infections may increase, with a risk of chronic lung damage and bronchiectasis. Whether early recognition with appropriate coordinated management may significantly reduce morbidity in advanced HIV disease deserves further study. ACKNOWLEDGEMENTS We thank Dr C Rizza and Dr P Giangrande for permission to report on their patients, and Dr J Hopkin and Dr F Gleeson for helpful discussion. REFERENCES 1. Hopkin JM. The suppurative lung diseases. In: Weatherall DJ, Ledingham JGG, Warrell DA, eds. Oxford Textbook of Medicine, Oxford: OUP, 1987; Polsky B, Gold JWM, Whimbley E et al. Bacterial pneumonia in patients with the acquired immunodeficiency syndrome. Ann Intern Med 1986; 104: Selwyn PA, Feingold AR, Hartel D et al. Increased risk of bacterial pneumonia in HIV-infected intravenous drug users without AIDS. AIDS 1988; 2: Mehle ME, Adamo JP, Mehta NC, Wiedemann HP, Keys T, Longworth DL. Endobronchial Mycobacterium aoium-intracellulare infection in a patient with AIDS. Chest 1989; 96:

882 AH Holmes and others 5. McCloud TC, Naidich DP. Thoracic disease in the immunocompromised patient. Radiol Clin N Am 1992; 30: 525-555. 6. Muller NL, Bergin CJ, Ostron DN, Nichols DM.

8 882 AH Holmes and others 5. McCloud TC, Naidich DP. Thoracic disease in the immunocompromised patient. Radiol Clin N Am 1992; 30: Muller NL, Bergin CJ, Ostron DN, Nichols DM. Role of computed tomography in the recognition of bronchiectasis. Am J Roentgenol 1984; 143: Grenier P, Maurice F, Musset D, Menu Y, Nahum H. Bronchiectasis: assessment by thin-section CT. Radiology 1986; 161: Ammann AJ, Schiffman G, Abrams D, Volberding P, Ziegler J, Conant M. B-cell immunodeficiency in acquired immunodeficiency syndrome. JAMA 1984; 251: Moskovic E, Miller R, Pearson M. High resolution computed tomography of Pneumocystis carinii pneumonia in AIDS. Clin Radiol 1990; 42: Valerius NH, Koch C, Heiby N. Prevention of chronic Pseudomonas aeruginosa colonisation in cystic fibrosis by early treatment. Lancet 1991; 338: Huang KL, Ruben FL, Rinaldo CR, Kinglsey L, Lyter DW, Ho M. Antibody responses after influenza and pneumococcal immunisation in HIV-infected homosexual men. JAMA 1987; 257: Steinhoff MC, Auerbach BS, Nelson KE etal. Antibody responses to Haemophilus influenzae type B vaccines in men with human immunodeficiency virus infection. New Engl J Med 1991; 325: The National Institute of Child Health and Human Development Intravenous Immunoglobulin Study Group. Intravenous immune globulin for the prevention of bacterial infection in children with symptomatic human immunodeficiency virus infection. New Engl J Med 1991; 325:

Hospital-acquired Pneumonia

Hospital-acquired Pneumonia Hospital-acquired pneumonia (HAP) Pneumonia that occurs at least 2 days after hospital admission. The second most common and the leading cause of death due to hospital-acquired