< Presentation of Case >
A 49-year-old man was seen because of increasing frequency of asthma for three months. He had been diagnosed as having asthma for two years, for which he regularly received inhaled beta adrenergic agonists. No allergens were identified before. He had been otherwise well until three months earlier when frequency of asthma increased, accompanied by allergic rhinitis which he ascribed it to prolonged working hours. In addition, he experienced a weight loss of 3 Kg within 3 months, low-grade fevers and non-productive cough. He also had dyspnea, decreased exercise tolerance, gradual onset of myalgia as well as paresthesias of both hands. At outpatient clinic, physical examination revealed a modest obese but well-developed man. Heart rate was 92 bpm, temperature was 37.8 ℃, blood pressure was 136/76 mmHg. There was no pale conjunctiva or icteric sclera. The heart beats were regular and cardiac auscultation did not show cardiac murmur. Auscultation of the lungs showed rhonchi at the left basal lung field. Bowel sounds were hyperactive. Mild periumbilical tenderness without peritoneal sign was noted. There was no shifting dullness or hepatosplenomegaly. No skin lesion was noted. The chest X-ray showed increased infiltration at the left lower lung and laboratory studies yielded leukocytosis with eosinophilia (see Laboratory). Urine analysis revealed proteinuria and hematuria (see Laboratory). Because of the low-grade fever and positive pulmonary findings in an ambulatory condition, an atypical pneumonia was suspected. He was first treated with oral azithromycin 1000 mg per day for 5 days. However, the symptoms did not improve; thus, he was admitted for further management.
1. CBC/DC:
|
Day after
admission
|
WBC
K/μL
|
Hgb
g/dL |
Hct
%
|
Plt
K/μL |
|
Seg
% |
Eos
% |
Lym
% |
OPD |
10.54 |
11.8 |
34.0 |
470 |
0 |
72 |
14 |
2.5 |
Admission |
10.84 |
11.9 |
33.8 |
472 |
0 |
72 |
15 |
2.4 |
Day 3 |
9.98 |
11.8 |
33.8 |
474 |
0 |
72 |
13 |
2.2 |
Day 7 |
9.23 |
11.8 |
33.7 |
463 |
0 |
74 |
12 |
2.3 |
Discharge |
7.23 |
11.6 |
33.7 |
465 |
0 |
71 |
10 |
2.3 |
2. Biochemistry:
Day after
hospitalization |
BUN
mg/dl |
Cre
mg/dl |
Na
mmol/l |
K
mmol/l |
AST
U/l |
ALT
U/l |
T-Bil
mg/dl |
OPD |
30 |
1.5 |
141 |
4.1 |
50 |
56 |
0.8 |
Admission |
44 |
1.6 |
141 |
4.1 |
50 |
56 |
0.8 |
Day 3 |
41 |
1.4 |
138 |
4.2 |
46 |
54 |
Not
Available
(NA) |
Day 7 |
NA |
NA |
NA |
NA |
42 |
45 |
NA |
Discharge |
24 |
1.3 |
138 |
3.9 |
37 |
35 |
NA |
Table 3. Urine analysis
| Date |
Appearance |
Specific
gravity |
pH |
Protein
(mg/dl) |
Glucose |
Ketone |
Occult
blood |
| OPD |
yellow, clear |
1.010 |
6.5 |
100 |
-- |
-- |
1+ |
| On admission |
yellow, clear |
1.010 |
6.5 |
100 |
-- |
-- |
1+ |
| Day 7 |
yellow, clear |
1.011 |
6.8 |
100 |
-- |
-- |
1+ |
| Discharge |
yellow, clear |
1.010 |
6.5 |
50 |
-- |
-- |
+/- |
| Date |
Urobilinogen |
Bilirubin |
RBC |
WBC |
Epithelial
cells |
Cast |
Bacteria |
| OPD |
0.1 |
-- |
10-20 |
<5 |
-- |
Granular |
-- |
| On admission |
0.1 |
-- |
>50 |
<5 |
-- |
Granular |
-- |
| Day 7 |
0.1 |
-- |
10-20 |
<5 |
1-3 |
Granular |
-- |
| Discharge |
0.1 |
-- |
5-10 |
<5 |
-- |
Granular |
-- |
4. Serology studies: C3, 92 (80 to 178 mg/dl); C4, 30 (12 to 42 mg/dl); c-ANCA, negative; p-ANCA, positive; rheumatoid factor, negative; ANA, negative.
5. CXR: increased infiltration at the left lower lung field. No cardiomegaly.
6. Renal sonography: Normal kidney size without hydronephrosis. No tumor or stone-like lesion.
7. Kidney biopsy: No globally sclerotic glomerulus was found, but 2 of out 12 had necrotizing fibrinoid necrosis. Mild interstitial fibrosis, focal tubular atrophy, interstitial edema as well as infiltration of lymphocytes, plasma cells and eosinophils were noted. Negative immunofluorescence studies and no electron-dense deposits were noted on electron microscopy. The pathological diagnosis was pauci-immune focal necrotizing glomerulonephritis.
< Course and Treatment >
Upon admission, the repeated chest X-ray showed no increased infiltration of the lungs compared to that obtained at the outpatient clinic, though the patient continued to have dyspnea. Meanwhile, newly developed erythematous macules, vasculitis-like lesions, were noted on the lower legs during the hospitalization, for which vasculitis was suspected. Since infection focus was not identified and vasculitis was likely to be the etiology. In addition, abnormal liver and renal functions were also suspected to be vasculitis-related. Renal biopsy was performed and it showed pauciimmune focal necrotizing glomerulonephritis. Based on a clinical history of asthma, eosinophilia, polyneuropathy, pathological findings and chest radiography, a diagnosis of Churg-Strauss syndrome was made. He responded well to methylprednisolone (15 mg/kg/d, IV bolus) for 3 days followed by oral prednisolone taper of 1 mg/kg. After the asthma was controlled and most laboratory abnormalities resolved, he was discharged with oral prednisolone.
< Analysis >
Allergic granulomatosis及angiitis (或稱為Churg-Strauss syndrome, CSS) 是一種全身性血管炎，發生率相當低，約每百萬人有2至4人，但因診斷不易，因此有被低估的可能。臨床上以氣喘、短暫性肺部浸潤、hypereosinophilia及全身性血管炎來表現。根據臨床上特定的表現，CSS可分為3期，每期具有不同的臨床特徵，雖然分為3期，但每期之間不一定具有順序性。早期的臨床表現以氣喘及伴隨(或無)過敏性鼻炎為主；第2期以週邊血液中eosinophilia增加及組織中eosinophils浸潤。第3期，或血管炎期，侵犯中小型動脈，而影響多種不同器官導致不同的臨床症狀。最常見被侵犯的器官為心臟，其他如肺、中樞神經、腎、肌肉神經等。另外有2/3的病患會有皮膚的侵犯。臨床上診斷CSS較困難，因為不同期別之間的表現不同且要在病理切片上同時見到eosinophils浸潤、壞死性血管炎(necrotizing vasculitis)及血管外肉芽腫(extravascular granulomas)不是很容易。American College of Rheumatology (ACR)曾發展出一套診斷標準來幫助診斷CSS: (1)氣喘 (2)周邊血液中有10%以上的eosinophilia (3) mononeuropathy或polyneuropathy (4)非固定性的肺部浸潤 (5)副鼻竇異常 (6)切片顯示血管伴隨血管外肉芽腫。若在6項中出現4項，則可達到85%的敏感性及99.7%的特異性，不過在1994年也有提出不同的標準 (Figure 1)，但不易量化。 CSS的病患中，男性病患比女性稍高一些，而平均發病年齡為50歲，但分布範圍相當大，任何年齡皆可能發病。儘管診斷不易，但經過適當治療，緩解率仍然相當不錯，而死亡病例多因為快速進展的血管炎。導致CSS的原因仍不是十分清楚，不過由於臨床表現和過敏關係十分密切，因此CSS被認為是一種過敏的過程。
要強調的是雖然臨床上分為3期，但各期之間並不一定有特定的順序，而臨床症狀的表現還是主要由被侵犯的器官決定。第一期(Allergic phase)是以氣喘、鼻炎或鼻竇症狀為主，並伴隨咳嗽或哮喘。氣喘、鼻炎或鼻竇炎可在發病前幾年就出現，而幾乎所有的病患都有氣喘的病史；第二期(eosinophilic phase)則以周邊血液中eosinophilia增加及組織中eosinophils浸潤造成的症狀為主，如體重減輕(常在血管炎期前)及常見的發燒及盜汗，另外也可能腹痛、腹瀉等。雖然在氣喘病患eosinophils大於800/uL並不少見，但當總數大於1500/uL或佔總白血球的10%時，就要高度懷疑CSS。第三期(vasculitic phase)則根據被侵犯的器官決定表現症狀，侵犯心臟以胸痛或喘表現；肺臟以咳嗽、哮喘或咳血；關節方面表現為肌肉關節疼痛及關節炎；神經方面主要是周邊神經病變 (65-75%) 以Mononeuritis multiplex為主，而以麻木或無力為主要表現。也有學者指出當一位氣喘並有eosinophilia的病患出現Mononeuritis multiplex時，幾乎可以確診CSS；腎臟方面以蛋白尿和血尿為主，不過大部分的預後在治療後都不錯，少腎衰竭；肌肉骨骼方面以關節腫脹及肌肉疼痛表現；皮膚方面以erythematous macules及類似erythema multiforme的斑塊及各式出血性皮膚表現(如petechiae、ecchymoses)、livedo reticularis及urticaria等。
診斷方面須與其他免疫疾病及血管炎做區分 (Figure 2)。除了病史、理學檢查外，實驗診斷及病理檢查可能是較重要的工具。風濕免疫學的檢查是必要的(如rheumatoid factor、antinuclear antibody、p-ANCA、c-ANCA及ESR等)，但並沒有一項十分好的標記可確定診斷，不過以p-ANCA為主。血液學方面，10%以上的eosinophilia是ACR其中一項診斷標準，較具特異性。其他如肝功能、腎功能、尿液檢查等，則可用以懷疑各器官是否被血管炎侵犯，胸部X光常見到浸潤。侵入性的檢查方面，皮膚及腎臟切片是最常被考慮的部位，若在組織切片上可見到血管炎、eosinophils浸潤、血管或血管外肉芽腫等，則更可支持CSS的診斷。儘管如此，CSS還是要靠高度的臨床懷疑，尤其是成年時才出現氣喘或過敏性鼻炎接著再出現全身性血管炎的病患。
治療方面主要以corticosteroids為第一線用藥，一般病患對藥物的反應十分好，在2星期內，eosinophilia及ESR多會恢復正常，多不需corticosteroids維持緩解，長期預後都不錯，但氣喘多仍持續。至於更嚴重的血管炎症狀或對corticosteroids反應不好，則要考慮使用cyclophosphamide。此外methotrexate、tumor necrosis factor (TNF)阻斷劑及recombinant interferon (IFN)-alpha也可使用。
本例中的病患，起初的氣喘或許就是CSS的最初表現，而之後再漸次出現過敏性鼻炎症狀及其他相關器官侵犯症狀，另外此病患之第二期與第三期之間的分界並不是十分清楚，也表示雖然臨床上分為3期，但各期之間並不一定有特定的順序。此病患主要是因為氣喘加劇才就醫，而其他相關器官侵犯症狀都被當成工時過長導致，這也顯示臨床上若不特別注意，確實不易診斷CSS。如文中所述，由於氣喘、10%以上的eosinophilia、mononeuropathy或polyneuropathy 及非固定性的肺部浸潤而診斷此病患罹患CSS。如果病理切片可見到血管炎(常侵犯小至中型血管)的證據、eosinophils浸潤、血管或血管外肉芽腫等，則更可支持CSS的診斷。雖然pANCA在CSS病患較易出現，但也不是每個病患都可被檢測出陽性。雖然皮膚及腎臟切片都可幫助血管炎的診斷，但選擇腎臟切片是因為既然懷疑腎臟被血管炎侵犯，腎臟切片除可提供腎臟受損程度之評估外，更可幫助預測腎臟預後，而這些都是皮膚切片所不足的。另外此病患對corticosteroids的反應十分好，之後在門診完全停藥也未再復發，但氣喘仍然持續，只是獲得控制，這也與多數報告類似。
< Reference >
1.JAMA. 2007;298(6):655-69
2.Lancet. 2003;361(9357):587-94
3.eMedicine
|
Case Discussion 
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