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Critical Care and Trauma: Research Reports

Acute Interstitial Pneumonia–Hamman-Rich Syndrome: Clinical Characteristics and Diagnostic and Therapeutic Considerations

Avnon, Lone S. MD*; Pikovsky, Oleg MD; Sion-Vardy, Neta MD; Almog, Yaniv MD§

Author Information
doi: 10.1213/ane.0b013e318188af7a

Acute interstitial pneumonia (AIP) is a rare interstitial lung disease (ILD) characterized by a rapid course frequently leading to respiratory failure and mechanical ventilation.1–3 Diagnosis is often difficult, possibly contributing to under-estimation of its incidence. Since it shares many similarities with the acute respiratory distress syndrome (ARDS), it could probably be classified as a subtype of ARDS.4 Histologically, AIP is characterized by diffuse alveolar damage (DAD), fibroblastic proliferation, and interstitial fibrosis.3 The exact mechanisms responsible for AIP are poorly understood; response to corticosteroids is usually limited and prognosis is grim.2 We describe nine patients with biopsy-proven AIP and discuss their clinical characteristics, course and management.

METHODS

This retrospective cohort study included all patients with AIP hospitalized between July 1998 and November 2006 at Soroka University Medical Center, which is the only tertiary, academic medical center serving the southern part of Israel. Patients’ records, radiologic studies, and pathologic specimens were reviewed. In order to be included in the study, patients had to meet the following predefined criteria, based on American Thoracic Society/European Respiratory Society International Multidisciplinary Consensus Classification of the Idiopathic Interstitial Pneumonias1: 1) rapidly progressive clinical course (<2 mo) leading to respiratory failure; 2) exclusion of infectious, toxic, autoimmune or any other known cause of ARDS; 3) DAD on biopsy specimens; 4) radiologic findings consistent with ILD; and 5) absence of chronic lung disease. All data were recorded in each patient’s study file and subsequently computerized. The study was approved by the IRB of Soroka University Medical Center before its initiation.

As a part of the work-up attempting to exclude other possible etiologies, mixed connective tissue disorder was excluded inpatient 4 by a negative anti URP 1 test. Patient 5 had an episode of hypersensitivity pneumonitis approximately 30 yr before his admission, from which he completely recovered. The lack of interstitial alveolar infiltrate with plasma cells and lymphocytes and the absence of noncaseating peribronchial granulomas in the biopsy specimen, as well as characteristic radiologic and clinical findings, led us to conclude that the current episode was related to AIP.

RESULTS

Our cohort consisted of 5 men and 4 women with a mean age of 69.4 yr. Their clinical characteristics are detailed in Tables 1. The initial clinical presentation was acute to subacute. Four patients had a history of constitutional symptoms and febrile illness lasting from a few days to 2 wk preceding their respiratory symptoms. Worsening shortness of breath and cough were the symptoms most often presented. Two patients presented while being treated with systemic steroids.

Table 1
Table 1:
Clinical and Demographic Characteristics of the Study Patients
Table 2
Table 2:
Diagnostic Evaluation, Management and Outcome of the Study Patients

Since presenting symptoms were rather nonspecific, it is not surprising that the initial clinical impression was diverse and misleading. Three patients were thought to have pulmonary embolism (Fig. 1), and three were thought to have pulmonary infection. Two patients were initially diagnosed with congestive heart failure. The mean time from the onset of symptoms to diagnosis was 12 days (range: 7–30 days). Our last patient (no. 9) was diagnosed on admission to the medical intensive care unit (MICU), probably reflecting our growing awareness.

Figure 1
Figure 1:
Figure 1.

The chest radiographs in all patients showed progression to diffuse bilateral infiltrates over a short period of time (Figs. 2, 3). Eight of nine patients underwent computed tomography scans of the chest, which revealed severe ground glass patterns, reticulo-nodular patterns, and air bronchogram (Fig. 4). Pleural effusion was also observed in five patients, and pericardial effusion in two (Fig. 1).

Figure 2
Figure 2:
Figure 2.
Figure 3
Figure 3:
Figure 3.
Figure 4
Figure 4:
Figure 4.

All patients underwent extensive evaluation of possible cardiac, infectious, autoimmune, and malignant causes that were carefully excluded. Pulmonary artery catheters were not inserted.

All nine patients had histological proof of DAD consistent with AIP. Seven trans-bronchial biopsies were performed (Fig. 5); in two patients the transbronchial biopsy was complicated by pneumothorax. Three patients underwent an open lung biopsy, two of them after a noninformative transbronchial biopsy.

Figure 5
Figure 5:
Figure 5.

All patients required admission to the MICU and mechanical ventilation. Patients’ lungs were carefully ventilated and treated with a lung-protective strategy as typically recommended in ARDS patients. All patients were treated with broad-spectrum antibiotics and with high-dose corticosteroid therapy (IV methylprednisolone 2 mg/kg 4 times a day). Three patients also received cyclophosphamide. All patients developed refractory hypoxemic and hypercarbic respiratory failure. The mortality rate was 100%, and patients died within 5–26 days of their admission to the MICU.

DISCUSSION

The ILDs comprise a heterogeneous group of conditions that involve the components of the lung parenchyma in varying proportions.1 The ILDs are nonmalignant, noninfectious disorders of various etiologies. Hamman and Rich5 were the first to describe four patients who died of a rapidly progressive lung disease characterized by diffuse interstitial pneumonia and fibrosis. In 1986 the term “acute interstitial pneumonia” was first introduced to describe a similar idiopathic clinical and pathological entity. Histologically, AIP is characterized by varying degrees of DAD, fibroblastic proliferation and interstitial fibrosis.1,3 The clinical features and course of AIP resemble ARDS.4 Likewise, the exact mechanisms responsible for the disease are poorly understood, and it is the clinical context in which these two entities appear that distinguishes them.2,4

A wide variety of conditions may present with similar clinical features. Consequently, diagnosing AIP may be difficult, and its exact incidence may be under-estimated due to under-diagnosis. The combination of acute onset, hypoxemia out of proportion to initial radiological findings, lack of identifiable cause, and later characteristic radiographic and pathological findings should alert the clinician to this distinct clinical entity.2,3,6 Moreover, the time from initial presentation to diagnosis is typically long, adversely affecting outcome. An early lung biopsy is required for a definitive diagnosis when AIP is suspected, and is of paramount importance in excluding other potentially treatable conditions such as infections, sarcoidosis, neoplasms, and other more commonly occurring ILDs.1 In fact, in previous studies diagnosis was established by open lung biopsy or after death.2,3,6 We successfully diagnosed four of our patients by transbronchial biopsy, suggesting that transbronchial biopsy is a simple and easily obtainable initial measure to support the clinical impression. It is debatable whether DAD can be diagnosed by small transbronchial biopsies. One may question a histopathological diagnosis of DAD obtained through flexible bronchoscopy with its tiny transbronchial biopsies; however, in our opinion when the characteristic features of DAD are identified in a patient clinically considered to have AIP, even the small transbronchial biopsies are diagnostic. Lung biopsies, whether transbronchial or open lung, are important auxiliary diagnostic tools when positive characteristics are identified. However, the absence of other treatable diseases in lung biopsies may be just as useful to the clinician and help to avoid unnecessary treatments. It should be emphasized that any biopsy should be interpreted within the clinical context of the patient. Therefore, biopsies are an important diagnostic tool.

Treatment of AIP is largely supportive, and consists of noninvasive or invasive ventilatory support.2,6–8 Most clinicians will try corticosteroids in doses ranging from 2 to 4 mg/kg, even though there are no convincing data to support this practice.2,3,6,7 Suh et al.8 used high-dose steroid pulse therapy consisting of 1 g/d IV methylprednisolone for 3 consecutive days followed by 1 mg · kg−1 · d−1 of IV methylprednisolone or oral prednisolone. Effectiveness of steroids is probably dependent on early diagnosis and the extent and ratio of inflammation to fibrosis at the time of diagnosis. Interestingly, two of our patients presented while being treated with systemic steroids. Some authors advocate the addition of immunosuppressive therapy, such as cyclophosphamide or vincristine.3 Given the rapid course of AIP and the extent of fibrosis typically evident in biopsies, these drugs are unlikely to affect the natural course at the late stages, when fibrosis is extensive.8

All of our patients died despite mechanical ventilation, supportive care and immuno-suppressive therapy. In some reports, patients’ ages were considerably younger than our cohort, and mortality rates ranged from 13% to 74%.3,7,8 We suspect that substantially different diagnostic criteria, co-morbid burden and case mix along with different genetic background account for this discrepancy.7 The exact prognosis of AIP is difficult to determine. Although some series report high mortality rate and limited response to corticosteroids or immunosuppressive therapy, others suggest a favorable response to treatment and better outcome (Tables 3). However, the time lost while waiting for an unlikely response to steroids may be crucial, particularly for those who are diagnosed relatively late in their course. Indeed, the importance of rapid diagnostic workup that may favorably affect outcome has been emphasized by others.8

Table 3
Table 3:
Summary of Previously Reported AIP Series
Table 4
Table 4:
Summary of Clinical Outcomes in Previously Reported AIP Series

All patients’ lungs were ventilated according to current guidelines emphasizing lung protection and limited airway pressure. Even though a lung-protective strategy was used, the mortality rate in our series remained exceedingly high. An important, fairly novel, modality in the management of patients with refractory hypoxemic and hypercarbic respiratory failure is a pumpless extracorporeal interventional lung assist device.9 It may facilitate gas exchange while avoiding ventilator-induced lung injury.

To our knowledge, lung transplantation has never been attempted during the acute phase of AIP. One report described three patients who developed progressive lung disease after an acute episode of AIP and were transplanted at a later stage.2 No data are available regarding possible recurrence of AIP in the transplanted lung. We propose that, despite its complexity and limited availability, lung transplantation may be considered in all patients with refractory AIP who fail to respond to medical management and are otherwise appropriate candidates.

In summary, AIP is an idiopathic, rapidly progressive, frequently fatal form of ILD similar to ARDS. A high index of suspicion is required, especially in patients with compatible clinical and radiologic findings resulting in respiratory failure of no apparent etiology. A transbronchial biopsy is a logical first step, to be followed by an open lung biopsy, if necessary. In those patients who fail to respond to corticosteroids, lung transplantation may be added to the therapeutic considerations.

REFERENCES

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