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Case Reports

Granulomatous Lung Disease as the Initial Presentation of Crohn Disease

Levenbrown, Yosef*; Tauber, Danna; Hall, Odette R; Baldridge, Alan D§

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Journal of Pediatric Gastroenterology and Nutrition: April 2009 - Volume 48 - Issue 4 - p 487-490
doi: 10.1097/MPG.0b013e31816b8cb2
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Crohn disease is an inflammatory disorder typified by noncaseating granulomas throughout the gastrointestinal tract. Although extraintestinal manifestations occur in 21% to 36% of patients and can affect almost any organ (1), pulmonary manifestations are extremely rare, occurring in fewer than 1% of patients (2). It is challenging to distinguish between atypical presentations of Crohn disease and other granulomatous diseases such as sarcoidosis. We present a case of a 15-year-old girl with recurrent respiratory symptoms who was found to have granulomatous inflammation throughout her lungs and gastrointestinal tract and was diagnosed as having pulmonary manifestations of Crohn disease.

CASE PRESENTATION

Our patient is a 15-year-old girl with a medical history significant for a recent diagnosis of anemia, diagnosed approximately 2 months before admission, who presented with a 2-week history of fatigue, a 1-month history of nonproductive cough, and 3 episodes of pneumonia during the previous 6 months. The first episode of pneumonia was diagnosed through chest radiograph findings; the second and third were diagnosed clinically. Although no history of fevers was reported, the patient did report frequent night sweats and a weight loss of 17 kg during the previous 6 months, with increasing exercise intolerance. Approximately 10 days earlier, the patient was sent for an abdominal CT after presenting to her pediatrician complaining of right lower quadrant abdominal pain. On the abdominal CT, it was discovered that she had bilateral basilar pulmonary nodules, a finding that was picked up incidentally because the lung bases were included at the upper margin of the abdominal CT. Because of this finding, CT was expanded to include her thorax and demonstrated peribronchovascular nodules as well as a mass-like infiltration throughout the lungs. At that point, the patient was admitted to the hospital for further workup.

Our patient's admission physical examination was significant for severely decreased breath sounds bilaterally, with a II/VI flow murmur that was detected at the upper right sternal border. Serum electrolytes with blood urea nitrogen and creatinine were within normal limits. White blood cell count was normal with a value of 10.3 × 109/L with a differential of 73% neutrophils, 0% bands, 17% lymphocytes, and 9% monocytes. The platelets count was normal at 281 × 109/L. However, the patient did have a hypochromic microcytic anemia with a hemoglobin concentration of 7.3 g/dL, a hematocrit of 27.5% with a low mean corpuscular volume of 63.5 mm3, a low mean corpuscular hemoglobin concentration of 26.7 g/dL, and a red blood cell distribution width that was high at 18.4%. Iron studies revealed iron deficiency anemia, with an iron level of 9 μg/dL (reference range 30–109) and a ferritin level of 8 ng/mL (reference range 10–70). Stool was negative for occult blood. Chest radiograph demonstrated multiple patchy areas of alveolar opacification bilaterally. A CT scan with contrast was performed to evaluate for mediastinal lymphadenopathy. It revealed numerous bilateral pulmonary parenchymal nodules involving all lung fields, as well as patchy bilateral infiltrates involving the right upper lobe, lingula, and left lower lobe, with no mediastinal lymphadenopathy noted (Fig. 1).

FIG. 1
FIG. 1:
Our patient's chest CT viewed in the lung window. Notice the multiple bilateral pulmonary parenchymal nodules of varying sizes involving all lung fields, as well as the bilateral pulmonary infiltrates. (Hematoxylin and eosin stain; original magnification ×40.)

On the third day of hospitalization, the patient's hemoglobin dropped to 6.7 g/dL, and she was transfused 2 U of packed red blood cells. Pulmonary function testing demonstrated poor function with a restrictive pattern, with forced vital capacity 43% of the predicted value, forced expiratory volume in 1 second 48% of the predicted value, and forced expiratory volume in 1 second/forced vital capacity 111% of the predicted value. The initial set of pulmonary function tests were of limited use, because at the time they were obtained the patient was unable to properly complete them because of dyspnea.

Further workup included a rapid human immunodeficiency virus test, tuberculin test, and serial blood cultures, all of which were negative. A transesophageal echocardiogram revealed no signs of vegetation on the heart valves. She also underwent bronchoscopy with bronchoalveolar lavage, with specimens sent for bacterial and fungal cultures, acid-fast bacilli stain and culture, as well as viral cultures and cytology, all of which were negative. A rheumatologic workup also was pursued including C- and P-anti-nuclear cytoplasmic antibodies, angiotensin-converting enzyme (ACE) level, anti-nuclear antibody, proteinase 3 antibody, myeloperoxidase antibody, Sjögrens antibodies (SSB and SSA), cardiolipin antibodies, double-stranded DNA antibodies, and Sm/anti-ribonucleoprotein antibodies, all of which were negative. Serum lysozyme level was slightly elevated at 13.4 μg/mL (reference range 4–10.3). ACE level was normal at 22 U/L (range 13–100). Dihydrorhodamine test to rule out chronic granulomatous disease was negative.

With a negative evaluation up to this point, the patient received a wedge lung biopsy. The biopsy showed a nodular mass with noncaseating granulomatous inflammation, including multinucleated giant cells, histiocytes, and acute and chronic inflammatory cell infiltrates. Occasional granulomas displayed areas of central necrosis. The inflammatory process was centered on the lung parenchyma; however, granulomatous inflammation also was seen involving the bronchioles. The remainder of the lung parenchyma adjacent to the nodule demonstrated a cryptogenic organizing pneumonia pattern (Fig. 2). Special stains for fungi, periodic acid Schiff, and Gomori methenamine silver were negative, as were stains for acid-fast bacilli.

FIG. 2
FIG. 2:
Section of lung showing noncaseating granulomatous inflammation with giant cells, as well as acute and chronic inflammatory cells. The inflammatory process involves the parenchyma and adjacent bronchiole on the right, which also demonstrates a cryptogenic organizing pneumonia pattern. (Hematoxylin and eosin stain; original magnification ×40.)

Focally necrotizing pulmonary sarcoid was considered as a possible etiology of the patient's symptoms. Because the patient's ACE level was on the low end of the normal range and the lung biopsy demonstrated features that were not typically seen in sarcoidosis, it was decided to evaluate the patient for Crohn disease with an upper endoscopy and colonoscopy. The visual findings of these studies were unremarkable other than an area of erythematous mucosa in the esophagus and a few superficial ulcers in the stomach. Biopsy samples were obtained from the proximal and distal esophagus, antrum, and duodenum, and random samples from the colon including the rectosigmoid portion. All of the areas biopsied demonstrated patchy areas of noncaseating granulomatous inflammation. In addition, chronic active gastritis was seen involving the antrum, and chronic active colitis was seen in the biopsies obtained from the random colon (Fig. 3).

FIG. 3
FIG. 3:
Section of the random colon biopsy demonstrating noncaseating granulomatous inflammation within the lamina propria. Acute cryptitis is seen in the lower left field.

The patient was placed on a treatment regimen for Crohn disease including solumedrol, methotrexate, and mesalamine. Pulmonary function tests were repeated 4 days after the treatments were initiated, and demonstrated mild improvement with forced vital capacity 47% of the predicted value and forced expiratory volume in 1 second at 53% of the predicted value. The patient was discharged home on prednisone, methotrexate, and mesalamine.

DISCUSSION

The similarity between Crohn disease and sarcoidosis has been well documented, given that they are both diseases with noncaseating granulomas affecting multiple organ systems. Although extraintestinal manifestations occur in 21% to 36% of patients with inflammatory bowel disease (1), the incidence of pulmonary complications is estimated to be less than 1%, with the majority of cases occurring in patients with ulcerative colitis (2). At the same time, the incidence of gastrointestinal involvement in sarcoidosis is equally as small, with an estimated prevalence of 0.1% to 0.9% (3).

We believe that the etiology of our patient's symptoms was secondary to pulmonary manifestations of Crohn disease, and as such, it appears to be the first case of a patient being diagnosed as having Crohn disease presenting with primarily pulmonary manifestations, without the classic gastrointestinal manifestations or the serological evidence of the disease. (Anti-Saccharomyces cerevisiae antibodies [ASCA] were negative.) In the majority of cases of pulmonary manifestations in Crohn disease, the pulmonary manifestations occurred after the onset of the gastrointestinal manifestations (4). In the 1 reported case of a patient with Crohn disease who presented with pulmonary findings preceding the gastrointestinal manifestations, the patient had already developed classic gastrointestinal symptoms of Crohn disease, including abdominal pain, diarrhea, and anal fissures before presenting to a physician. In addition, whereas in the case reported the patient's ASCA level was strongly positive for immunoglobulin G and A, our patient's was negative. Although not diagnostic because of a moderate sensitivity of 50% to 80%, ASCA level is highly specific for Crohn disease, occurring in fewer than 10% of patients with ulcerative colitis and fewer than 5% of healthy controls (5).

In attempting to distinguish between Crohn disease with pulmonary manifestations and sarcoidosis with gastrointestinal manifestations, we found a number of factors pointing to Crohn disease. The most important factor was the ACE level. Previous studies trying to distinguish between uncommon manifestations of these 2 diseases have consistently pointed to the serum ACE level as a major distinguishing factor. In a study of 463 patients comparing serum ACE level in patients with sarcoidosis versus patients with other granulomatous diseases, with both groups compared with controls, the serum ACE level was significantly higher in patients with active sarcoidosis when compared with controls, with a sensitivity of 92% and a negative predictive value of 95.2% when looking at the presenting serum ACE levels of patients with active sarcoidosis. The false negative rate was only 7.9% (6). In contrast, the serum ACE level in patients with Crohn disease has consistently been reported to be normal to low, especially during periods of active disease (7–9). Extrathoracic disease, multiple organ disease, and a chest radiograph demonstrating interstitial lung disease were factors that were associated with an elevated serum ACE level in patients with sarcoidosis (6). All 3 of these elements were present with our patient, and as such should increase the negative predictive value of her low ACE level of 22 (reference range 13–100). Furthermore, iron deficiency anemia is a hallmark of Crohn disease and is not associated with sarcoidosis (2,7). Anemia in patients with sarcoidosis has been reported in 2 cases; in 1 case it was caused by reflux esophagitis and in the second case it was caused by hematochezia (7). Being that our patient's stools were heme-occult negative on a number of occasions and there was no other source for her bleeding, her iron deficiency anemia was attributed to her underlying disease, a factor that fits with Crohn disease and not sarcoidosis. In addition, the lack of superficial or radiographic lymphadenopathy in our patient was more consistent with Crohn disease than sarcoidosis.

Histology is not a reliable discriminating factor between sarcoidosis and Crohn disease because the pattern of granulomatous inflammation is similar and even commonly described as “sarcoid-like.” Nonspecific histological features of sarcoidosis, including Shaumann bodies and asteroid bodies, were not seen in this case. However, these entities are seen in only 48% to 88% and 2% to 9% of sarcoid cases, respectively. In addition, although the granulomas seen in sarcoidosis are typically non-necrotic, small areas of necrosis within granulomas have been described previously in sarcoid (10). Polymorphonuclear cell infiltrates within the gastric pits and colonic crypts, as were seen in our patient's biopsy, are not well described in sarcoidosis, which appears to favor the diagnosis of Crohn disease. Finally, in addition to the fact that sarcoidosis itself is rare in children, disseminated gastrointestinal sarcoidosis has not been described previously in children, and even in the adult population occurs rarely (2).

This report of a patient being diagnosed as having Crohn disease after presenting with pulmonary manifestations without typical gastrointestinal or serological evidence of the disease is significant on a number of fronts. First, this case highlights the importance of considering the diagnosis of Crohn disease and obtaining a gastrointestinal diagnostic evaluation, including an upper and lower endoscopy with biopsies on patients who present with granulomatous diseases of unknown etiology or containing atypical features, even without serological evidence or typical gastrointestinal features of Crohn disease. Additionally, because it was felt that our patient's underlying disease process was Crohn disease, her treatment regimen included mesalamine, a treatment used for Crohn disease, in addition to methotrexate and prednisone, thus highlighting the importance of distinguishing between the 2 diseases from a therapeutic standpoint. If her treatment regimen of prednisone, methotrexate, and mesalamine would have failed, then she could have been treated with an alternative treatment for Crohn disease, including infliximab, which has been documented in previous case reports to be extremely effective in treating pulmonary manifestations of Crohn disease (4).

Acknowledgments

The authors would like to thank Jean-Pierre DeChadarevian, MD, for contributions to this article and Herb Rosen for help with the graphics.

REFERENCES

1. Juillerat P, Mottet C, Froehlich F, et al. Extraintestinal manifestations of Crohn's disease. Digestion 2005; 71:31–36.
2. Al-Binali AM, Scott B, Al-Garni A, et al. Granulomatous pulmonary disease in a child: an unusual presentation of Crohn's disease. Pediatric Pulmonol 2003; 36:76–80.
3. Sharma AM, Kadakia J, Sharma OP. Gastrointestinal sarcoidosis. Sem Respir Med 1992; 13:442–449.
4. Krishnan S, Banquet A, Newman L, et al. Lung lesions in children with Crohn's disease presenting as nonresolving pneumonias and response to infliximab therapy. Pediatrics 2006; 117:1140–1143.
5. Neilsen OH, Vainer B, Madsen SM, et al. Established and emerging biological activity markers of inflammatory bowel disease. Am J Gastroenterol 2000; 95:359–367.
6. Ainslie GM, Benatar SR. Serum angiotensin converting enzyme in sarcoidosis: sensitivity and specificity in diagnosis: correlations with disease activity, duration, extra-thoracic involvement, radiographic type and therapy. Q J Med 1985; 218:253–270.
7. Beniwal RS, Cummings OW, Cho WK. Symptomatic gastrointestinal sarcoidosis—case report and review of the literature. Dig Dis Sci 2003; 48:174–178.
8. Weaver LJ, Simonowitz D, Driscoll R, et al. Serum angiotensin converting enzyme in patients with Crohn's disease. J Surg Res 1980; 29:475–478.
9. Dumot JA, Adal K, Petras RE, et al. Sarcoidosis presenting as granulomatous colitis. Am J Gastroenterol 1998; 93:1949–1951.
10. Gal AA, Koss MN. The pathology of sarcoidosis. Curr Opin Pulm Med 2002; 8:445–451.
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