Prune belly syndrome

Clinical Features and Outcomes

Introduction: Pulmonary alveolar proteinosis (PAP) is a rare disease of unknown etiology and variable natural history. To date, the largest series from a single institution has consisted of 68 individuals. To extend the understanding of the clinical features and natural history of PAP, we present a series of 24 patients with PAP from a single institution.

Methods: Patients with PAP were identified by a review of The Cleveland Clinic Foundation discharge database from 1965 to 1995. After identification, a chart review of the 24 selected patients was conducted. Charts were abstracted for historical, diagnostic, and therapeutic features. Diagnosis was confirmed by a review of the lung biopsy, where it was available, by a lung pathologist. Follow-up by telephone was performed with 19 patients.

Results: Most patients (70%) were male, and smoking was common (75%; mean pack-years, 29) in the group. The mean age at initial evaluation was 43 years. Presenting symptoms were as follows: 19 patients (79%) reported dyspnea, 19 patients (79%) reported a cough, 4 patients (17%) reported hemoptysis, and 3 patients (13%) reported chest pain. The earliest available spirometry after presentation of symptoms showed a prediction of mean [FEV.sub.1] of 74% (range, 45 to 99%) and a prediction of mean FVC of 76% (range, 41 to 99%). The diagnosis of PAP was established by transbronchial biopsy alone in 7 patients (29%) and by open-lung biopsy alone in 17 patients (71%). Whole lung lavage was deemed necessary in 13 patients (54%); 3 patients underwent lavage of one lung only, and 10 patients underwent bilateral whole lung lavage. Whole lung lavage was required only once in 46% of patients, and from two to four times in the remainder of patients. During the follow-up period (mean length of follow-up, 8.5 years; range, 5 months to 21 years), 25% of the patients died, but none as a result of sequelae of PAP. Half of the survivors reported persistent symptoms.

Conclusions: In this series, which represents one of the largest single institutional experiences with PAP reported, the clinical features are largely consistent with previously reported cases. However, contrary to early reported experiences in which open-lung biopsy was frequently required to establish PAP and in which whole lung lavage was needed, transbronchial biopsy established the diagnosis in 29% of patients and whole lung lavage could be deferred in 46% of patients. (CHEST 1998; 114:1357-1362)

Key words: clinical features; pulmonary alveolar proteinosis; whole lung lavage

Abbreviations: DLCO = diffusion capacity of the lung for carbon monoxide; GM-CSF = granulocyte-macrophage colony-stimulating factor; LDH = lactate dehydrogenase; Pa[O.sub.2] = arterial partial pressure of oxygen; PAP = pulmonary alveolar proteinosis

First reported by Rosen et al[1] in 1958, pulmonary alveolar proteinosis (PAP) is an uncommon disorder that is characterized by the accumulation of proteinaceous material within alveoli. As with many uncommon diseases, the cumulative experience with PAP is sparse, with only 139 patients in the largest single report and with, to our knowledge, 332 total patients reported in the literature. Table 1 presents the features of patients involved in series with [is greater than or equal to] 24 subjects.

(*) Series with 24 or more patients.

([dagger]) Remaining patients in first two studies were diagnosed solely on clinical grounds.

([double dagger]) NA = not available.

([sections]) Denotes percentage of patients with FVC [is less than] 80% predicted.

([parallel]) Denotes percentage of patients with DECO [is less than] 70% predicted.

([paragraph]) Denotes percentage of patients with Pa[O.sub.2] [is less than] 80 mm Hg.

Available reports highlight several persisting uncertainties regarding both the natural history of and the optimal therapy for PAP. Specifically, an early report by Summers[2] on 93 patients suggested a 39.7% mortality rate due to hypoxic respiratory failure or complicating diseases during a follow-up period of up to 17 years. In contrast, recent experiences from both the Mayo Clinic and from Japan suggest mortality rates of 8.8%[3] and 0,[4] respectively.

There also is uncertainty about the methods of diagnosis and treatment for PAP. An early series by Davidson and Macleod[5] advocates diagnosis by thoracotomy or trocar biopsy, whereas the more recent experience of Asamoto et al[4] reports successful diagnosis by bronchoscopy in 89.7% of 68 cases. The role of bronchoscopy in establishing the diagnosis of PAP remains controversial.

Finally, the possibility of spontaneous resolution of PAP has made clinical decision-making about treatment with whole lung lavage more difficult.[6] Indeed, the frequency with which whole lung lavage has been required to effect clinical improvement has been variable in prior reports.

To expand available experience with PAP and to better describe the presenting clinical features and natural history of PAP, the current study characterizes our experience with 24 consecutive patients with PAP. This descriptive study also was undertaken as a prelude to an open-label trial of a new therapy using granulocyte-macrophage colony-stimulating factor (GM-CSF) injection.

Materials and Methods

To ascertain eligible eases, a list of patients designated under Diagnosis-Related Group 519.2 (PAP) in the hospital database was assembled. Inclusion criteria were the presence of PAP as confirmed by a physician diagnosis and a consistent lung biopsy. All available slides were reviewed by a lung pathologist (Dr. Farver) to confirm the diagnosis of PAP.

The medical records of eligible patients were reviewed by one of the study investigators, and data elements were extracted using a standard data collection instrument. The presenting symptoms were those that were evident at the initial referral to an outside institution or, in patients new to the Cleveland Clinic, signs and symptoms that were evident at the initial assessment at our institution. Patients and/or family members were contacted by telephone to ascertain follow-up clinical information and to assess long-term outcomes.

Results

Twenty-four patients with PAP were identified (17 were male, 7 were female). Their mean age ([+ or -] SD) was 42 [+ or -] 13.5 years (range, 21 to 67 years of age), and 18 patients were current or former smokers at the time of the initial presentation (mean pack-years, 29). All patients were white. One of the following systemic diseases was present in each of five patients (21%): breast cancer, myelodysplasia, pericardial disease, inflammatory bowel disease, and prune belly syndrome. No patients were known to be infected with HIV, though testing was not undertaken routinely. In the group, 12 patients were laborers (without silica exposure), 2 patients were secretaries, 2 patients were students, 2 patients worked in the computer industry, and 1 patient each was an attorney, a businessman, a hairstylist, a teacher, a waitress, and a homemaker.

The most common symptoms at presentation were dyspnea and cough, both of which were present in 79% of patients (Table 2). Physical examination revealed rales in 50% of patients,[7] clubbing in 25%,[6] and cyanosis in 21%.[5] The plain chest radiograph showed an alveolar-filling pattern in most patients (62.5%; Table 3). Infiltrates were mostly diffuse but showed a perihilar distribution in six patients. Spirometry and lung volumes revealed a mild restrictive ventilatory defect with a mean FVC of 75% predicted and a mean total lung capacity of 74% predicted (Table 4). However, the diffusion capacity was disproportionately and severely reduced (mean [[+ or -] SD] was 47 [+ or -] 17% predicted) among the eight patients tested. Patients were mildly hypoxemic (Table 4) with a mean room air Pa[O.sub.2] of 66 [+ or -] 14.1 mm Hg and a mean alveolar-arterial gradient of 50.7 [+ or -] 57.1 mm Hg. The serum lactate dehydrogenase (LDH) was mildly elevated, with a mean of 393 [+ or -] 72 IU/L (range, 166 to 959 IU/L).

(*) Some patients with [is greater than] 1 symptom, 80 total exceeds 100%.

(*) TLC = total lung capacity.

([dagger]) Normal range is 0-220.

Fifteen of 24 (62.5%) patients underwent a total of 19 bronchoscopies. The median time from the onset of symptoms to diagnosis was 9.5 months. Bronchoscopic biopsies established the diagnosis in 7 patients, although 3 patients required a second bronchoscopy to secure the diagnosis (37% of bronchoscopies were positive). One patient underwent two nondiagnostic bronchoscopies. Alternately, the diagnosis of PAP was established by open-lung biopsy in the eight patients who had nondiagnostic bronchoscopies and in nine other patients in whom open-lung biopsy was performed without a prior bronchoscopy. No patient required more than one open-lung biopsy for diagnosis. For the 20 patients with symptoms, no infectious etiologies for PAP were identified in our patients.

Whole lung lavage was deemed necessary by the managing physicians over a mean follow-up interval of 8.4 years (range, 5 months to 21 years) in 13 patients (54%). Universal indications for whole lung lavage were dyspnea and/or hypoxemia. Deterioration revealed in chest radiographs alone was not an indication for whole lung lavage in this series, but it did confirm clinically apparent deterioration in several patients. Altogether, 13 patients underwent a total of 43 whole lung lavages over the course of their illness (mean, 3.3 lavages/patient; range, 2 to 8 lavages/patient). For 34 of the whole lung lavages for which data were available, the mean lavage volume was 11.8 [+ or -] 3.68 L. Lavage return volumes were available for 29 procedures (mean 10.2 [+ or -] 3.92 L). Six of the 13 patients (46%) underwent lavage only during the first year after their diagnosis. The other 7 patients needed repeated whole lung lavages, but among the 11 patients followed for more than 10 years, only 1 required lavage more than 10 years after the initial diagnosis was made. The remaining 10 patients were followed for 10 years (range, 3 to 17 years) and did not require whole lung lavage.

As is shown in Table 5, whole lung lavage led to improved oxygenation or to reduced oxygen requirements in 83% of the 30 procedures for which data were available. Spirometry results were available before and after whole lung lavage therapy for nine patients, with four showing a slight improvement in FVC (mean rise, 11%). Four patients had their FVC worsen after whole lung lavage (mean decrease, 6.5%). Of the four patients who had diffusion capacity measurements before and after whole lung lavage, three showed improvement. Chest radiographs reportedly were improved in 58% of 12 instances in which post-whole lung lavage reports were available for review.

[TABULAR DATA 5 NOT REPRODUCIBLE IN ASCII]

Additional therapies included pancreatic enzyme supplementation, either as a stand-alone therapy (4 patients) or with whole lung lavage (2 patients), and corticosteroids (offered with pancreatic enzyme supplementation and whole lung lavage in 1 patient).

Follow-up information over a mean period of 9.8 years (range, 1 to 21 years) was available for 21 patients and consisted of hospital records (9. patients) and telephone contact with the patient or family (19 patients). The hospital records indicated that both patients had died (though details regarding the cause of death were unavailable). Four of the 19 patients for whom telephone follow-up was available had died, but none had died of complications from PAP. Nine of the remaining 15 patients (60%) reported persistent symptoms: 8 reported dyspnea, 6 reported cough, 1 reported chest pain, and 1 reported wheezing.

Discussion

This study extends the available experience with PAP (Table 1) and also makes several new observations. As in prior reports, PAP was more common among men than women, with typical onset in the fifth decade of life. As in the reports by Rosen et al[1] and Prakash et al,[3] dyspnea also was a common presenting symptom among patients in the current series. Also, physical examination was largely unrevealing; the pulmonary physiologic profile of our patients was that of mild restriction with a disproportionate decrease in the diffusing capacity. A mild elevation of LDH was commonly present.

In contrast to results from earlier studies,[3,4] a cough was more common as a presenting symptom (79% of our patients vs 24% and 59% of patients in earlier series, respectively). Furthermore, a cough occurred in the absence of dyspnea in 17% of our patients. Also, few of our patients were asymptomatic, which likely was due to the bias reflected in their being referred to a tertiary care institution (frequently for whole lung lavage) in this series. Fewer patients in the current series had underlying systemic diseases or dust exposures (eg, silica) than previously described,[8] though this may be explained by under-reporting in the medical record and by our retrospective chart review. In marked contrast to older series in which infectious complications (eg, nocardiosis or Pneumocystis carinii pneumonia) were reported in 15 to 20% of subjects,[9] none of the 9.4 patients in our series experienced opportunistic pulmonary infections over the course of a mean 9.8 years of follow-up. Furthermore, the examination of whole lung lavage fluid in 13 of our 24 patients showed no evidence of infectious organisms. A similar absence of infectious complications was reported by Claypool et al[10] in a series of 34 patients.

The features in our patients that were revealed by radiography are consistent with prior reports. Alveolar infiltrates were most common, followed in frequency by interstitial and nodular infiltrates. Although none of the patients in our series underwent chest CT, prior reports suggest that CT may demonstrate the extent and pattern of PAP more dearly than the plain radiograph.[7,11] The report by Godwin et al[7] noted that airspace disease was the most common pattern (88%) revealed on chest CT, though reticular interstitial infiltrates were also common (67%). No pathognomonic patterns on chest CT were apparent in that series.

Our experience suggests an enhanced diagnosis of PAP currently, as the interval between symptom onset and initial diagnosis was [is less than or equal to] 1 year for 12 of the 20 symptomatic patients for whom information was available. In contrast, in 1983, Dubois et al[12] reported a median time to diagnosis of 2 years in their series of 10 patients. This accelerated diagnosis likely reflects both enhanced diagnostic suspicion of PAP by current practitioners and improved diagnostic techniques.

In this regard, our series confirms an evolving diagnostic trend in which bronchoscopy is supplanting open-lung biopsy as the initial diagnostic method for PAP. In a 1969 report by Davidson and Macleod.[5] open-lung biopsy was uniformly performed to establish this diagnosis. Diagnosis was made with bronchoscopy in 11 and 83% of eases, respectively, in reports from 1987 and 1988.[3,13] The more recent work of Mahut et al[4] also confirms the role of bronchoscopy in diagnosing PAP in eight pediatric patients. While the diagnostic sensitivity of bronchoscopy was lower in our series than in that of Rubinstein et al,[13] our experience confirms the value of an initial diagnostic bronchoscopy. Furthermore, the suggestive characteristics of BAL fluid in PAP augment the value of bronchoscopy in PAP.[11] In comparing the fluid of 10 subjects with PAP (5 who were in remission) to that of 33 individuals with other lung diseases, Martin et al[15] found the BAL fluid in PAP to be distinctly opaque and milky, with microscopic features of diffuse eosinophilic staining, large eosinophilic bodies, and fewer alveolar macrophages. Surfactant proteins A and D have recently been reported to be elevated in the BAL fluid of patients with PAP. Though unavailable in the current series, the measurement of these proteins has been advocated as enhancing the bronchoscopic diagnosis of PAP.[16,17]

In the current therapeutic era, another remaining uncertainty about PAP is the need for whole lung lavage, especially because of the variable natural history of the disease (which includes spontaneous remissions) and because potential alternative treatments are emerging.[18,19]

Regarding the variable natural history, our experience shows that a large minority of patients (46%) followed over a prolonged period never required whole lung lavage. At the same time, some patients, including 29% in our series, require repeated whole lung lavage for recurring signs and symptoms of PAP. Our series serves as a reminder that predicting the natural history of PAP and predicting the ultimate need for whole lung lavage remain elusive tasks. At the same time, there are some exciting new prospects for potential adjunct, or even alternative, therapies to whole lung lavage. A model of mice deficient in GM-CSF has been shown to develop a pulmonary abnormality that closely resembles PAP histologically.[20,21] To further understand the potential role of stimulating alveolar macrophages, Huffman et al[22] showed that providing the gene for GM-CSF to the respiratory epithelium of these deficient mice corrected the PAP. Bone marrow transplantation and hematopoietic reconstitution of GM-CSF-deficient mice has been shown to reverse this abnormality.[23] In the context of these animal studies, it is tempting to speculate that injecting GM-CSF would favorably affect the clinical course of PAP. In fact, Seymour et al[24] recently reported a single ease of a cross-over experience in which the administration of GM-CSF was associated with improved gas exchange in a patient with PAP, with subsequent worsening after the withdrawal of GM-CSF. Furthermore, readministration of GM-CSF was again associated with clinical improvement. On the basis of this theoretical benefit and the encouraging single case experience, our group has planned an open-label study of GM-CSF treatment for mild to moderate PAP. The current description of the variable natural history and the spectrum of clinical severity reminds us that there are patients for whom GM-CSF, if found effective, might be a useful treatment alternative to whole lung lavage. However, as with the assessment of whole lung lavage, evaluating the efficacy of GM-CSF for treatment of PAP will be made difficult by the variable natural history of this disorder and will require careful study, ideally in a multicenter randomized trial.

References

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[13] Rubenstein I, Mullen JBM, Hoffstein V. Morphologic diagnosis of idiopathic pulmonary alveolar lipoproteinosis-revisited. Arch Intern Med 1988; 148:813-816

[14] Mahut B, Delacourt C, Scheinmann P, et al. Pulmonary alveolar proteinosis: experience with eight pediatric cases and a review. Pediatrics 1996; 97:117-122

[15] Martin RJ, Coalson JJ, Rogers RM, et al. Pulmonary alveolar proteinosis: the diagnosis by segmental lavage. Am Rev Respir Dis 1980; 121:819-825

[16] Honda Y, Takahashi H, Shijubo N, et al. Surfactant protein-A concentration in bronchoalveolar lavage fluids of patients with pulmonary alveolar proteinosis. Chest 1993; 103:496-499

[17] Honda Y, Kuroki Y, Matsuura E, et al. Pulmonary surfactant protein D in sera and bronchoalveolar lavage fluids. Am J Respir Crit Care Med 1995; 152:1860-1866

[18] Danel C, Israel-Bier D, Costabel U, et al. Therapeutic application of bronchoalveolar lavage. Eur Respir J 1992; 5:1173-1175

[19]] Walsh FW, Rumbak MJ. The technique of whole lung lavage. J Crit Illness 1996; 11:191-197

[20] Stanley E, Lieschke GJ, Grail D, et al. Granulocyte/macrophage colony-stimulating factor-deficient mice show no perturbation of hematopoiesis but develop a characteristic pulmonary pathology. Proc Natl Acad Sci USA 1994; 91:5592-5596

[21] Dranoff G, Crawford AD, Sadelain M, et al. Involvement of granulocyte macrophage colony-stimulating factor in pulmonary homeostasis. Science 1994; 264:713-716

[22] Huffman JA, Hull WM, Dranoff G, et al. Pulmonary epithelial cell expression of GM-CSF corrects the alveolar proteinosis in GM-CSF-deficient mice. J Clin Invest 1996; 97:649-655

[23] Nishinakamura R, Wrier R, Dirksen U, et al. The pulmonary alveolar proteinosis in granulocyte macrophage colony-stimulating factor/interleukin 3/5 [Pi]c receptor-deficient mice is reversed by bone marrow transplantation. J Exp Med 1996; 183:2657-2662

[24] Seymour JF, Dunn AR, Vincent JM, et al. Efficacy of granulocyte-macrophage colony-stimulating factor in acquired alveolar proteinosis [letter]. N Engl J Med 1996; 335:1924-1925

(*) From the Departments of Pulmonary and Critical Care Medicine and Pathology, Cleveland Clinic Foundation, Cleveland, OH.

Manuscript received November 12, 1997; revision accepted April 21, 1998.

Correspondence to: James K. Stoller, MD, FCCP, Department of Pulmonary and Critical Care Medicine, Desk A90, Cleveland Clinic Foundation, 9500 Euclid Avenue, Cleveland, OH 441951; e-mail: stollej@cesmtp.ccf.org

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