Dear Bloggers
I have been fortuitous to have received several most excellent workups of the recent case, all with the correct diagnosis! I have included the replies below.
One reply was from a 6th year medical student, Hirotaka Kato of Kumamoto University. This is the first time a medical student has answered a blog case and I hope this sets a precedent whereby other medical students and junior doctors feel they can contribute to future case answers. Medical students are always most welcome to reply.
Q1.
# cough and severe dyspnea
# SpO2 88%
# wheezes on bilateral sides
# bilateral pleural effusions on CXR
# rash on left arm and chest
# right eyelid and facial swelling
# finger numbness, (decreased sensation)
# dull/ right upper abdominal pain
# past history of asthma, nasal polyp, chronic sinusitis
etc.
Q2.
I suspected vasculitis first from the positive findings,
but I had no confidence because of no fever, no elevated
leukocytes.
Second, I thought of allergic diseases.
Allergy can explain no fever, but I wonder if Allergy
could cause finger numbness.
Though it was hard for me to decide the priority of
suspected diseases, my differential diagnosis became the
following,
# Churg-Strauss syndrome
# ABPA (allergic bronchopulmonary Aspergillosis)
# severe asthma attack such as aspirin-induced asthma
# dermatomyositis
# drug allergy
Q3.
The diagnostic test is measuring MPO-ANCA.
Besides, eosinophil count, aspergillus antigen and so on.
Q4.
steroid pulse therapy could relieve his symptoms.
The next response is from Dr Gerald Stein, University of Florida.
Question 1: From the history, physical examination, radiology and laboratory data, please make a list of the positive findings.
1 Cough and dyspnoea,wheezing2 Facial swelling4 Dull abdominal pain
3 Arm and chest rash with pruritis
5 Finger numbness
6 Chronic Sinusitis (30 years)
13 Mother had tuberculosis7 Asthma (life long)10 Recurrent Eyelid and Facial swelling (from 5 years before)
8 Nasal polyp operation (8 years ago)
9 Recurrent Urticarial-like skin rashes (from 5 years before)
11 Autoimmune Haemolytic Anaemia (AIHA) treated with steroid pulse therapy 3
years before.
12 Urinary stones (5 years before)
14 Resp Rate 18/min, SpO2 88% breathing ambient room air.17 Sensation decreased in the finger tips of both hands
15 percussion decreased at both bases. Wheeze throughout both lungs R>>>L. Few crackles at both bases.16 Abdomen: tender right hypochondrium and epigastrium.
18 Chest Radiograph: Bilateral pleural effusions
Question 2: Please give a likely list of differential diagnoses based on your list generated in question 1.
Churg-Strauss Syndrome with resp, GI, neuro & skin involvement
DDx ASA sensitivity syndrome-nasal polyps, asthma,
vasculitis: micro polyangiitis [no renal]
Wegeners {does not occur in Japanese}
SLE
HIV
Tuberculosis
HCV
CA with paraneoplastic syndrome
Question 3: What tests would you perform to ascertain the diagnosis?
Immune markers: RF, anti-CCP, ANA, ss, sd ANA, ANCA(P&C). Eosinophil count absolute and %, skin Bx, possible sural nerve Bx, HIV Ab, Tb skin test, sputum smear & CULTURE for Tb, HCV Ab, stool occult blood, FiberColon with Bx; later consider thoracocentesis if no Dx from earlier tests, spirometry with DL CO, sinus CT, Chest CT, haptoglobin, nerve conduction study
Questions 4: With the likeliest diagnosis in mind, what is the treatment of the disorder?
The last expert opinion is from Dr Masami Matsumura, Kanazawa University Medical School.
Thank you very much for showing me a challenging case again! This patient has history of several disorders, especially autoimmune diseases. The fact that this patient has history of asthma alludes the key of the diagnosis. His first symptom is a one-month history of productive cough with following symptoms of heart failure with or without worsening of asthma. Interestingly, he has finger numbness again! His history doesn’t indicate possibility of diabetes. Mononeuritis multiplex or polyneuropathy is highly suspected in this case. Probably he has mononeuritis multiplex. A rare vascullitis is suspected.
Question 1: From the history, physical examination, radiology and laboratory data, please make a list of the positive findings.
#1 Cough
#2 Dyspnea
#3 Hypoxia
#4 Wheezing
#5 Crackles at both bases
#6 Cardiomegaly
#7 Right abdominal pain
#8 Facial swelling
#9 Skin rash with pruritis
#10 Sensation decreased in the finger tips of both hands
#11 Anemia
#12 Increased platelets
#13 Pleural effusions
#14 Asthma
#15 Paranasal sinus abnormality
#16 Recurrent Urticarial-like skin rashes
#17 Recurrent Facial swelling
#18 Autoimmune Haemolytic Anaemia
#19 Family history of tuberculosis
Positive findings from #1 to #6 and #13 showed cardiac failure with or without an asthmatic component. Positive finding of #10 indicates of possibility of a mononeuritis multiplex. Polyneuropathy is less likely because he doesn’t have symptom in the feet. Positive findings #11 and #12 means a chronic inflammatory process.
#2 Dyspnea
#3 Hypoxia
#4 Wheezing
#5 Crackles at both bases
#6 Cardiomegaly
#7 Right abdominal pain
#8 Facial swelling
#9 Skin rash with pruritis
#10 Sensation decreased in the finger tips of both hands
#11 Anemia
#12 Increased platelets
#13 Pleural effusions
#14 Asthma
#15 Paranasal sinus abnormality
#16 Recurrent Urticarial-like skin rashes
#17 Recurrent Facial swelling
#18 Autoimmune Haemolytic Anaemia
#19 Family history of tuberculosis
Positive findings from #1 to #6 and #13 showed cardiac failure with or without an asthmatic component. Positive finding of #10 indicates of possibility of a mononeuritis multiplex. Polyneuropathy is less likely because he doesn’t have symptom in the feet. Positive findings #11 and #12 means a chronic inflammatory process.
Question 2: Please give a likely list of differential diagnoses based on your list generated in question 1.
Differential diagnoses are as follows.
Vascular: Less likely
Infection: HIV, TB
Neoplastic: Lymphoma, Paraneoplastic syndrome
Autoimmune: Churg-Strauss syndrome, Wegener’s glanulomatosis, Microscopic polyangiitis, Polyarteritis nodosa, Goodpasture’s syndrome, SLE, Sarcoidosis, Waldenström’s macroglobulinemia, Cryogloblinemia
Toxic/Metabolic: Less likely
Trauma/Degenerative: Less likely
Iatrogenic: Less likely
Idiopathic: Amyloidosis
Congenital: Less likely
My most likely diagnosis is Churg-Strauss syndrome (CSS).
Second candidate is Wegener’s granulomatosis.
Both disorders are very uncommon in Japan!! CSS is very rare disease. Estimated annual occurrence is 1 –3 per million.
The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome are as follows:
1: Asthma
2: Eosinophilia >10%
3: Neuropathy, mono or poly
4: Pulmonary infiltrates, non-fixed
5: Paranasal sinus abnormality
6: Extravascular eosinophils
* For classification purposes, a patient shall be said to have Churg-Strauss syndrome if at least 4 of these 6 criteria are positive. The presence of any 4 or more of the 6 criteria yields a sensitivity of 85% and a specificity of 99.7%.
Masi AT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990; 33:1094-100.
This patient has three criteria, asthma, mononeuritis multiplex, and paranasal abnormality. I would confirm white cell differentials first.
CSS can cause multi-system disorders, paranasal sinus, lung, cardiac, skin, GI-tract, or neurologic. Cardiac involvement is suspected in this patient because he has cardiac failure. Eosinophils can infiltrate cardiac muscle. This phenomenon should be removed as soon as possible.
I would introduce one clinical pearl.
“Leukotriene inhibitors such as montelukast, given for asthma, have been implicated as causing some cases of Churg‐Strauss syndrome”
This patient doesn’t take leukotriene inhibitors.
Vascular: Less likely
Infection: HIV, TB
Neoplastic: Lymphoma, Paraneoplastic syndrome
Autoimmune: Churg-Strauss syndrome, Wegener’s glanulomatosis, Microscopic polyangiitis, Polyarteritis nodosa, Goodpasture’s syndrome, SLE, Sarcoidosis, Waldenström’s macroglobulinemia, Cryogloblinemia
Toxic/Metabolic: Less likely
Trauma/Degenerative: Less likely
Iatrogenic: Less likely
Idiopathic: Amyloidosis
Congenital: Less likely
My most likely diagnosis is Churg-Strauss syndrome (CSS).
Second candidate is Wegener’s granulomatosis.
Both disorders are very uncommon in Japan!! CSS is very rare disease. Estimated annual occurrence is 1 –3 per million.
The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome are as follows:
1: Asthma
2: Eosinophilia >10%
3: Neuropathy, mono or poly
4: Pulmonary infiltrates, non-fixed
5: Paranasal sinus abnormality
6: Extravascular eosinophils
* For classification purposes, a patient shall be said to have Churg-Strauss syndrome if at least 4 of these 6 criteria are positive. The presence of any 4 or more of the 6 criteria yields a sensitivity of 85% and a specificity of 99.7%.
Masi AT, et al. The American College of Rheumatology 1990 criteria for the classification of Churg-Strauss syndrome (allergic granulomatosis and angiitis). Arthritis Rheum 1990; 33:1094-100.
This patient has three criteria, asthma, mononeuritis multiplex, and paranasal abnormality. I would confirm white cell differentials first.
CSS can cause multi-system disorders, paranasal sinus, lung, cardiac, skin, GI-tract, or neurologic. Cardiac involvement is suspected in this patient because he has cardiac failure. Eosinophils can infiltrate cardiac muscle. This phenomenon should be removed as soon as possible.
I would introduce one clinical pearl.
“Leukotriene inhibitors such as montelukast, given for asthma, have been implicated as causing some cases of Churg‐Strauss syndrome”
This patient doesn’t take leukotriene inhibitors.
Question 3: What tests would you perform to ascertain the diagnosis?
I would order white cells differentials, ESR, Urinalysis, ANA, C3, CH50, P-ANCA, C-ANCA, EKG, and cardiac echo.
Skin biopsy should be performed, if patient agrees. I would confirm of infiltration of eosinophils and/or vasculitis.
Questions 4: With the likeliest diagnosis in mind, what is the treatment of the disorder?
Skin biopsy should be performed, if patient agrees. I would confirm of infiltration of eosinophils and/or vasculitis.
Questions 4: With the likeliest diagnosis in mind, what is the treatment of the disorder?
If diagnosis is correct, oral prednisolone is indicated. This treatment will be successful. I would add one point. He has family history of TB. Patient’s symptoms and chest radiograph should be carefully monitored for reactive TB.
Case Diagnosis The answers to the above questions are absolutely correct. The patient did have a diagnosis of the Churg-Strauss Syndrome. However, the ANCA was negative. The patient agreed to have a skin biopsy and indeed, it did reveal vasculitis. The peripheral eosinophil count was raised and the percentage was 15%.
Despite several weeks of Prednisolone at dose of 50mg/day with initial resolution of symptoms and signs, the patient had a recrudescence of cough and skin rash prompting the introduction of cyclophosphamide.
Churg Strauss Syndrome (CSS)
This is a vasculitis of small and medium sized arteries. It classically involves the arteries of the lung and skin (as in this case) but as Dr Matsumura has pointed out it may affected other organs too.
Epidemiologically, CSS shows no difference in gender with mean age of diagnosis around 50 years. Aetiology is unknown although it is regarded as an autoimmune process because of the predominance of allergic features, increased T and B cell activity, presence of ANCA and an association with HLA subtypes.
On reviewing the literature in respect of leutriene antagonists, it is considered that the drugs probably do not directly cause CSS. However, because these drugs are used in asthma with the aim to reduce steroid use, by so reducing the corticosteroid dose probably unmasks true CSS rather than the leukotriene antagonist causing the CSS-like syndrome.
The CSS can take many decades to fully manifest the full spectrum of features and patients generally have a long history of allergic disease e.g. asthma, atopic disease followed by an eosinophilic stage characterised by peripheral eosinophilia and organ infiltration with eosinophils. The final stage is the vasculitic stage.
A history of asthma is the cornerstone to the diagnosis as most patients will have had asthma for up to a decade before the diagnosis of CSS is made.
Most patients require steroid therapy for their asthma and severity and frequency of exacerbations may increase over time. 2/3 of patients develop skin involvement in the vasculitic stage and generally affect the limbs and may manifest as palpable purpura, macular or papular erythematous eruption, haemorrhage, tender cutaneous or subcutaneous nodules (granulomas).
Indeed, the heart can be affected in the CSS with manifestations including pericarditis, heart failure and AMI. 50% of deaths are related to cardiac disease from the CSS, so it is not a trivial finding.
Neurological manifestations are usually as a mononeuritis multiplex which can progress if the CSS is left untreated. Renal disease can also manifest with the commonest problem being focal segmental glomerulonephritis. Gastrointestinal disease may occur as an eosinophilic gastroenteritis.
Most CSS patients (70-75%) have ANCA against myeloperoxidase (P-ANCA). However, this patient was ANCA negative. In a small analysis it was indicated that there may be a difference between ANCA + and ANCA - patients with the former having more renal involvement and more neuropathy whereas the latter having more heart disease and fever associated with their condition.
Note that this patient had bilateral effusuions. 30% of patients with CSS actually have effusions and analysis usually reveals eosinophils and an exudative composition. As Dr Matsumura has correctly pointed out, the American College of Rheumatology guidelines offer a way to make the diagnosis. In fact, in view of the positive biopsy result, this patient had at least four of the six criteria making the diagnosis of CSS extremely likely.
Treatment is indeed with corticosteroids at a dose of 0.5-1.5 mg/kg/day for 6-12 weeks or until the disease manifestations have completely resolved. The higher dose is required especially if there is cardiac, renal or nerve involvement.
Refractory CSS (as in this case) may be helped with the addition of cyclophosphamide, azathioprine, immune globulin or alpha-interferon. However, some authorities recommend an induction treatment of steroid plus cyclophosphamide and for remission to be maintained with methotrexate or azathioprine. Monitoring of disease is via the eosinophil count and ESR --- not ANCA.
Prognosis: With adequate treatment, 5 year survival > 70%. Most deaths result from complications of the vasculitic phase and include heart failure / AMI, cerebral bleeding, azotaemia, GI bleeding and life threatening asthma.
I would again like to thank everyone for their significant contributions to answering this case. For a more detailed review of the CSS, I would refer you to UpToDate 16.2, Current Medical Diagnosis and Treatment 2008 (McPhee, Papadakis and Tierney) and the Oxford Handbook of Rheumatology, 2nd Edition, 2006 (Hakim, Clunie and Haq).
Have a great week !!!
Case Diagnosis The answers to the above questions are absolutely correct. The patient did have a diagnosis of the Churg-Strauss Syndrome. However, the ANCA was negative. The patient agreed to have a skin biopsy and indeed, it did reveal vasculitis. The peripheral eosinophil count was raised and the percentage was 15%.
Despite several weeks of Prednisolone at dose of 50mg/day with initial resolution of symptoms and signs, the patient had a recrudescence of cough and skin rash prompting the introduction of cyclophosphamide.
Churg Strauss Syndrome (CSS)
This is a vasculitis of small and medium sized arteries. It classically involves the arteries of the lung and skin (as in this case) but as Dr Matsumura has pointed out it may affected other organs too.
Epidemiologically, CSS shows no difference in gender with mean age of diagnosis around 50 years. Aetiology is unknown although it is regarded as an autoimmune process because of the predominance of allergic features, increased T and B cell activity, presence of ANCA and an association with HLA subtypes.
On reviewing the literature in respect of leutriene antagonists, it is considered that the drugs probably do not directly cause CSS. However, because these drugs are used in asthma with the aim to reduce steroid use, by so reducing the corticosteroid dose probably unmasks true CSS rather than the leukotriene antagonist causing the CSS-like syndrome.
The CSS can take many decades to fully manifest the full spectrum of features and patients generally have a long history of allergic disease e.g. asthma, atopic disease followed by an eosinophilic stage characterised by peripheral eosinophilia and organ infiltration with eosinophils. The final stage is the vasculitic stage.
A history of asthma is the cornerstone to the diagnosis as most patients will have had asthma for up to a decade before the diagnosis of CSS is made.
Most patients require steroid therapy for their asthma and severity and frequency of exacerbations may increase over time. 2/3 of patients develop skin involvement in the vasculitic stage and generally affect the limbs and may manifest as palpable purpura, macular or papular erythematous eruption, haemorrhage, tender cutaneous or subcutaneous nodules (granulomas).
Indeed, the heart can be affected in the CSS with manifestations including pericarditis, heart failure and AMI. 50% of deaths are related to cardiac disease from the CSS, so it is not a trivial finding.
Neurological manifestations are usually as a mononeuritis multiplex which can progress if the CSS is left untreated. Renal disease can also manifest with the commonest problem being focal segmental glomerulonephritis. Gastrointestinal disease may occur as an eosinophilic gastroenteritis.
Most CSS patients (70-75%) have ANCA against myeloperoxidase (P-ANCA). However, this patient was ANCA negative. In a small analysis it was indicated that there may be a difference between ANCA + and ANCA - patients with the former having more renal involvement and more neuropathy whereas the latter having more heart disease and fever associated with their condition.
Note that this patient had bilateral effusuions. 30% of patients with CSS actually have effusions and analysis usually reveals eosinophils and an exudative composition. As Dr Matsumura has correctly pointed out, the American College of Rheumatology guidelines offer a way to make the diagnosis. In fact, in view of the positive biopsy result, this patient had at least four of the six criteria making the diagnosis of CSS extremely likely.
Treatment is indeed with corticosteroids at a dose of 0.5-1.5 mg/kg/day for 6-12 weeks or until the disease manifestations have completely resolved. The higher dose is required especially if there is cardiac, renal or nerve involvement.
Refractory CSS (as in this case) may be helped with the addition of cyclophosphamide, azathioprine, immune globulin or alpha-interferon. However, some authorities recommend an induction treatment of steroid plus cyclophosphamide and for remission to be maintained with methotrexate or azathioprine. Monitoring of disease is via the eosinophil count and ESR --- not ANCA.
Prognosis: With adequate treatment, 5 year survival > 70%. Most deaths result from complications of the vasculitic phase and include heart failure / AMI, cerebral bleeding, azotaemia, GI bleeding and life threatening asthma.
I would again like to thank everyone for their significant contributions to answering this case. For a more detailed review of the CSS, I would refer you to UpToDate 16.2, Current Medical Diagnosis and Treatment 2008 (McPhee, Papadakis and Tierney) and the Oxford Handbook of Rheumatology, 2nd Edition, 2006 (Hakim, Clunie and Haq).
Have a great week !!!
Posts
