CLINICO-PATHOLOGICAL CONFERENCE
A 73-year-old man with confusion, fever,and positive MPO-ANCA
Hiroshi Nagata, Ken Teramoto, Akira Suwa, Takato Abe, Tokuhiro Kimura1 and Rie Shibata1
Departments of Internal Medicine and 1Pathology, School of Medicine, Keio University, Tokyo, Japan(Received for publication on July 24, 2003)

Abstract. A 73-year-old man was admitted to the hospital because of progressive lethargy and fever.
He had a history of hypertension since the age of 40, and was diagnosed as having a testicular tumor at
the age of 50. On admission, he looked pale and stuporous. Laboratory examination revealed microscopic hematuria. The erythrocyte sedimentation rate was 110 mm/hr, and the serum CRP was 14.3
mg/dl. The titer of myeloperoxidase-antineutrophilic cytoplasmic antibodies (MPO-ANCA) was higher
than 1 : 1000. On the sixth hospital day, he required ventilatory assistance because of aspiration pneumonia and was connected to a respirator. He was treated with intravenous corticosteroids, to which heresponded in the short term with resolution of the fever and decrease in the serum CRP level, however,the consciousness disturbance persisted and the fever recurred soon thereafter. He developed grosshematuria and the renal function deteriorated. He eventually died of renal failure and pulmonary
hemorrhage. Although his clinical course and laboratory ﬁndings were consistent with those of microscopic polyangitis, the pathological diagnosis was crescentic glomerulonephritis with no evidence ofvasculitis. (Keio J Med 53 (2): 103–114, June 2004)
Key words: vasculitis, microscopic polyangitis, confusion, ANCA, hematuria

Dr. Nagata (Moderator): We shall now start the
1072nd Clinico-pathological Conference (CPC) of ourinstitution. Dr. Teramoto, the physician-in-charge ofthe patient, will give us a clinical presentation of thepatient.
Dr. Teramoto (Internal Medicine): The patient was a73-year-old man with the chief complaints of pyrexia
and consciousness disturbance.
Concerning the history of present illness, the patient
had suffered from occasional arthralgia, low grade fever, and generalized malaise since around 1999, but
he had been able to continue to keep house until October 2000. On October 31, 2000, he was vaccinatedagainst inﬂuenza and three days after the vaccination he developed generalized muscle aches and easy
fatigability. He became unable to carry on with his
household activities, and visited Johsai Hospital for examination on November 14, 2000. Hematological examination at that hospital revealed an increase in theserum C-reactive protein (CRP) level to 5.20 mg/dl, anda high serum g-globulin level. Thereafter, he visited afamily physician on November 28, where he was suspected as having senile depression. Hematological examination at this clinic revealed a further increase in
the serum CRP level to 8.60 mg/dl, and the hemoglobin(Hb) level was 10.2 g/dl. He became unable to carryon with the activities of daily living (ADL), and tired
easily, even while talking or eating meals. When it became difﬁcult for him to be understood by others, hiswife who was herself suffering from schizophrenia andwas a regular outpatient at the Department of Psychiatry of our hospital, took him to the department for
examination on December 22, 2000. He was admitted
to the psychiatry department on the same day, and was
immediately started on intravenous hyperalimentation
to improve his nutritional status. Despite this, however,his consciousness disturbance persisted and his generalcondition remained unchanged. Pyrexia of 38.0–38.9 C
was also recorded. Since malignant tumor, collagendisease, or infection, rather than a psychiatric disease,
was suspected as the cause of the consciousness disturbance, the patient was referred to the Department ofThis is a record of the 1072nd CPC of Keio University Hospital, held on June 25, 2003.
Reprint requests to Dr: Hiroshi Nagata, Departments of Internal Medicine, School of Medicine, Keio University, 35 Shinanomachi, Shinjukuku, Tokyo 160-8582, Japan
103

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Gastroenterology on December 28, 2000, for further
investigation and management.
Concerning the patient’s past history, he had had
pulmonary tuberculosis at about 20 years of age, appendicitis at about 30 years of age, and was diagnosed
as having a gastric ulcer and hypertension during thefourth decade of life. However, detailed information
regarding the treatment of the hypertension could not
be obtained. He was diagnosed as having a testiculartumor at about 50 years of age. Finally, at the age of 72,
he had undergone excision of a colonic polyp.
In regard to his personal history, he was not a
habitual smoker or drinker.
Concerning his family history, both his wife anddaughter suffered from schizophrenia. There was nofamily history of allergy.
Mr. Inokuchi (6th grade student): Was there any history of weight loss? Were any purpuric rashes observedat any point of time during the clinical course?
Dr. Teramoto: No details regarding weight loss orobservation of purpuric rashes were available at thetime of admission, but both the clinical signs were noted
during the patient’s stay after admission to the hospital.
Dr. Nagata: We can probably assume that the patient
had weight loss, since he became unable to eat daily
meals. His general condition at the time of admission
was extremely poor, and he looked tired and emaciated. Under these circumstances, he could certainly
be assumed to have lost considerable weight.
Dr. Teramoto: As for purpura, FOY was used during the course of treatment, and purpura appeared ataround the time that it was started.
Dr. Nagata: The purpura appeared after admission,and I suppose we can assume that it was absent at thetime of admission.
Dr. Suwa (Internal Medicine): This patient had apast history of hypertension; do you know any details of
his medication at the time of admission?
Dr. Teramoto: When he was admitted to our hospital, he was receiving oral Nifedipine.
Dr. Nagata: Did he have asthma or any symptoms ofbronchitis?
Dr. Teramoto: He had no clinical features of any infection, of pneumonia in particular, or of asthma.
Dr. Nagata: Did he give you a history of tooth extraction before admission?
Dr. Teramoto: No.
Dr. Nagata: So, in this patient, we must ﬁrst resolve
the issue of time of onset of the disease. Since 1999 orso, he had had arthralgia, low grade fever, and generalized malaise. However, his ADL were maintained. It
is difﬁcult to say whether the symptoms were triggeredby the prophylactic vaccination against inﬂuenza that
he received on October 31, 2000, but he developed serious constitutional symptoms, including muscle aches,

Nagata H, et al: A man with confusion, fever, and positive MPO-ANCA

easy fatigability and generalized malaise from November 3, about 3 days after the vaccination, and was foundto have elevated serum levels of inﬂammatory markers.
When do you think the present disease process set in?
Dr. Teramoto: I would not be able to comment on
the precise time of onset of his disease, but in view of
his age, the symptoms that appeared 3 days after thevaccination may be assumed to be related to pyrexia
following the vaccination. I believe it is possible that thepatient developed acute disseminated encephalomyelitis (ADEM). We shall discuss this further while we talkabout the differential diagnosis in this patient.
Dr. Nagata: Three days after the vaccination against
inﬂuenza, he developed severe generalized malaise andmuscle aches, much like the symptoms of a common
cold, am I right?
So, Dr. Teramoto, will you now please tell the audience about the patient’s condition on admission?
Dr. Teramoto: The patient’s examination ﬁndings on
admission were as follows: His height was 172 cm andbody weight was 65 kg. His consciousness was I-3 on
the Japan Coma Scale (JCS). His blood pressure was
160/64 mmHg at the time of being referred to the Department of Internal Medicine; the pulse rate was 84
per minute, and the body temperature was 37.2 C. Mildanemia was present, but there was no jaundice. No signiﬁcant abnormalities were found on oral examination.
The heart sounds were regular, and lung examination
did not reveal any abnormalities. There was edema
over the lower extremities. Nuchal rigidity was G. There
was no tremor at rest. The pupils were equal, and 3.0–
3.9 mm in diameter. There was no nystagmus or double
vision. The papillary light reﬂex was normal on bothsides. There were no signiﬁcant abnormal ﬁndings on
neurological examination. Babinski’s sign was negative.
Neither Chaddock’s reﬂex nor Hoffmann’s reﬂex was
observed. Manual muscle testing (MMT) revealed aslight reduction of power, but it was assumed to bemostly within the normal range. There were no sensory
abnormalities, including pain perception. The muscle
strength was slightly decreased.
Dr. Nagata: Was there a right-left difference in the
blood pressure of this patient?
Dr. Teramoto: No, there was no signiﬁcant right-leftdifference in the blood pressure.
Dr. Nagata: Were there any heart murmurs?
Dr. Teramoto: No, there was no heart murmur.
Dr. Nagata: Was any bruit heard over the abdomenor chest?
Dr. Teramoto: No, there were no bruits over theabdomen.
Dr. Nagata: According to your presentation, thepatient did not have any purpura. Were there any skinrash or subcutaneous nodes?
Dr. Teramoto: There were no signiﬁcant abnormal

Keio J Med 2004; 53 (2): 103–114
Table 1

Laboratory Test Results during Admission[Laboratory ﬁndings on admission] (On admission) [Occult blood]3þ, [Urinalysis] pH 6.5, Glu 1þ, Pro G, Bld 3þ, Ket , Nit , Leu ,
Bil , Uro G, Many RBCs, WBC classiﬁcation <2, CAST neg., E-C
neg., Bac. neg., [Peripheral blood] WBC 8,500/ml (Band. þ, Seg.
84.5%, Lymph. 12.7%, Mono. 1.6%, Eosino. 0.8%, Baso. 0.4%),
RBC 27,900/ml, Hb 7.5 g/dl, Ht 24.3%, Plt 264,000/ml, MCV 87 ﬂ,
MCH 26.9 pg, MCHC 30.9 g/dl, Retics 120, [Coagulation system]
APTT 30.3 sec., PT-sec. 14.0 sec., PT-% 51%, PT-INR 1.45, FNG
421 mg/dl, FDP 692 ng/ml, D-dimer 8.3, ESR b 110 mm/h,[Biochemistry] TP 8.0 g/dl, ALB 2.9 g/dl, TC 143 mg/dl, TB 0.8 mg/
dl, DB 0.2 mg/dl, Cre 1.1 mg/dl, UA 5.6 mg/dl, Na 135.2 mEq/l, K
3.6 mEq /l, Cl 99 mEq/l, Ca 7.7 mg/dl, LDH 384 IU/l, GOT 36 IU/l,
GPT 18 IU/l, Alp 156 IU/l, g-GTP 17 IU/l, ChE 126 IU/l, Glu
139 mg/dl, CRP 14.30 mg/dl, ferritin 1090 ng/ml, Fe 17 mg/dl, TIBC
171 mg/dl, UIBC 154 mg/dl, measurement of protein demarcation Alb
38.3% #, a1 5.3% ", a2 12.8% ", b 9.4%, g 34.2% ", A/G 0.62 #, IgG
1940 mg/dl, IgA 378 mg/dl, IgM 67 mg/dl, C3 74 mg/dl, C4 29 mg/dl,
CH50 6.0 U//ml, VB12 1012 pg/ml ", FA 7.6 ng/ml, [Tumor markers]
CA 19-9 9 U/ml, CEA 3.2 ng/ml, SCC 1.3 ng/ml, PA 1.8 ng/ml, PAP
0.8 ng/ml, [Others] HbsAg (), HCV Ab (), 40-fold positive ANA,
Pattern SPE, RF <11, anti-DNA antibody <10.0, MPO-ANCA
1000<, IC-C1q <1.5, IC-C3d 14.5, negative CRYO-G, ASO <53,
IGG-RF 0.3, anti-RNP antibody 8.1, anti-SSA antibody 4.8, S.IL-2R
1420 U/ml ", negative lupus anticoagulant, [Urinary cytodiagnosis]
Class II, [Lumbar puncture] Cell count 1, mono 1, poly 0, protein
52 mg/dl, Cl 129 mEq /l, glucose 89 mg/dl, IgG 13.6 mg/dl, negative
general bacterial culture, negative tubercle bacillus cultureﬁndings on dermatological examination at the time ofadmission.
Dr. Nagata: You mentioned that the patient had
been diagnosed as having a testicular tumor; was there
any enlargement of the testicles at the time of admission?
Dr. Teramoto: No, no testicular enlargement wasnoticed in the patient at the time of admission.
Dr. Nagata: Will you then please explain the laboratory ﬁndings of the patient on admission (Table 1).
Dr. Teramoto: The laboratory ﬁndings of this patienton admission were as follows: Stool tested positive(þþþ) for occult blood. Urinalysis revealed the presence of many red blood cells (RBCs) and less than 2
white blood cells (WBCs) per high power ﬁeld. There
were no casts. Peripheral blood examination revealed a
WBC count of 8,500/ml, with marked predominance ofneutrophils. The Hb was 7.5 g/dl and the platelet (Plt)count was 264,000/ml. All the values were within normal
limits. As for the blood coagulation proﬁle, the activated partial thromboplastin time (APTT) was 30.3
sec., within the normal range.
On the other hand, the serum ﬁbrinogen level was
slightly elevated. The serum level of ﬁbrin degradation
products (FDP) was also elevated. The serum D-dimer
level was elevated to 8.3. The erythrocyte sedimentation rate (ESR) was markedly increased at 110 mm/

105h. Blood biochemical examination revealed a slightly
decreased serum albumin level. Other tests revealed
the following signiﬁcant ﬁndings: the serum ferritin
level was increased to 1,090 ng/ml, and the serum Fe
concentration was decreased to 17 mg/dl. The serum
vitamin B12 (VB12) level was elevated. There wasno signiﬁcant increase in the level of any of the tumor
markers. The antinuclear antibody titer was 1 : 40, witha SPEC pattern, suggesting that it was slightly above
the normal range. The serum titer of MPO-ANCA wasmarkedly increased to more than 1 : 1000. The serum
immune complex (IC)-C1q level was less than 1.5, andthat of IC-anti-C3d was 14.5, suggestive of a slight increase over the normal range. The serum was negative
for cryoglobulins (CRYO-G), as well as for lupus anticoagulant. A lumbar puncture was also conducted, andCSF examination revealed a cell count of 1, which wasa mononuclear cell. The protein level was 52 mg/dl,
within the normal range. Glucose was also within thenormal range. As for culture of the CSF, both cultures
for pyogenic organisms and for tubercle bacilli were
negative.
Mr. Ito (Y: Yujiro) (6th-grade student): Both theserum albumin and serum cholinesterase levels
were decreased. The patient might have had liver
dysfunction – is that possible?
Dr. Teramoto: The patient meal intake was very
poor because he got extremely tired while eating. So, he
was assumed to have had malnutrition.
Ms. Ueda (6th-grade female student): How about thelevel of BUN?
Dr. Teramoto: It (BUN) was 25.6 mg/dl, slightly
high.
Dr. Suwa: Did you conduct testing for HBsAg andhepatitis C virus (HCV) antibody? When was the
MPO-ANCA measured?
Dr. Teramoto: Yes, we did the tests for HBsAg and
HCV antibody – both were negative. The MPO-ANCA
was measured soon after the patient’s condition suddenly deteriorated early in the following year. The
results were obtained around mid-January.
Dr. Nagata: You mentioned that the ESR was highon admission. It was markedly elevated, wasn’t it?
Dr. Shibata (Pathology): Was the serum titer of antibasement membrane antibody measured?
Dr. Teramoto: No, it was not measured at the time ofadmission.
Mr. Ito (Y.): Examination of the cerebrospinal ﬂuid
(CSF) revealed an increase in the IgG level. What do
you think of that?
Dr. Abe (Internal Medicine): The normal level of
IgG in the CSF is approximately 5–6 mg/dl. Basedon this, the IgG level in this patient can be considered
as being elevated. In the presence of infections, forinstance, including meningitis, the CSF IgG level is106

increased. As for other diseases, it may occasionallybe elevated in cases of autoimmune angiitis, systemic
lupus erythematosus (SLE) and central nervous system(CNS) lupus, which are all collagen vascular diseases,
and in multiple sclerosis (MS), a disease of the CNS.
Since there was no increase in the CSF cell count, theincreased IgG level may have reﬂected an autoimmune
pathological condition.
Dr. Teramoto: Let me now explain to you the X-rayﬁndings in this patient. A chest X-ray revealed no abnormal ﬁndings, including no evidence of pneumonia.
No cardiomegaly was noted either. This is an X-ray
taken on December 23, 2000, the day after his admission to the hospital. This X-ray was taken on February
5, 2001, just before the patient died. It shows hazinessof both lung ﬁelds. Since bloody sputum was aspirated
from the endotracheal tube, the haziness of the lungﬁelds was attributed to pulmonary hemorrhage.
This is an X-ray of the abdomen taken in the prone
position. It revealed a slight increase in the large intestinal gas shadow, but there were no other ﬁndings, suchas an increase in the small intestinal gas shadow, which
would have been indicative of ileus.
Dr. Nagata: Dr. Abe, could you comment on theﬁndings on magnetic resonance imaging (MRI) of thehead of this patient?
Dr. Abe: The patient had consciousness disturbanceand pyrexia of at least 38 C. There seems to have beenno distinct focal neurological deﬁcit, but the patient
did have mild nuchal rigidity. He was suspected of having an inﬂammatory lesion of the CNS, and a lumbar
puncture was conducted. No increase in the CSF cellcount was found. Therefore, MRI was conducted to
exclude inﬂammatory or space-occupying lesions in thehead.
No space-occupying lesion is observed in any of theimages. Diffuse cerebral atrophy is observed, but there
is no distinct diagnostic pattern that would allow precise
determination of the cause of dementia on this image,and the atrophy is not localized, which is a typical ﬁnding in Alzheimer’s disease or Pick’s disease. Coronal
sections were also obtained, but no deﬁnite lesions wereidentiﬁed.
Dr. Teramoto: These are computed tomographic(CT) images of the abdomen, showing a transverse section across the epigastric region of the abdomen. Mild
pleural effusion is observed bilaterally. Other ﬁndings
include the presence of ascitic ﬂuid around Gerota’s
fascia anterior to the kidney. Since ascitic ﬂuid has
more or less the same CT density as blood, hemorrhage
cannot be ruled out. A left renal cyst is also present.
The CT revealed no evidence of massive hemorrhage,
as a particular cause of the anemia.
Dr. Nagata: So, there were no speciﬁc imaging ﬁndings that might help us to make a diagnosis; no space-

Nagata H, et al: A man with confusion, fever, and positive MPO-ANCA

occupying lesions and no signs of chronic inﬂammation.
Right?
Dr. Teramoto: Yes.
Dr. Nagata: Here was a patient who was a 73-yearold man – a man of fairly advanced age. What was thegeneral clinical course of this patient?
Mr. Ito (C: Chihiro) (6th-grade student): From theﬁndings, the course may be assumed to be subacute.
Dr. Nagata: There was a relatively distinct onset ofsymptoms on October 31, 2000, and the patient diedin February, 2001. The patient was of fairly advanced
age, and his overall clinical course was subacute in nature, although after admission, he appears to have had
a rather fulminant course. The patient was referred to
the Department of Internal Medicine on December 28,
2000, after which his general condition rapidly deteriorated. The physician-in-charge may have administeredsymptomatic therapy for this patient.
What was the differential diagnosis considered at the
Department of Internal Medicine? What were the distinctive clinical features of the patient?
Mr. Ito (C.): The patient had a history of arthralgia,
low grade fever, generalized malaise, persistent feverof unknown cause, consciousness disturbance, and hisstool was positive for occult blood.
Dr. Nagata: The clinical presentation was characterized by nonspeciﬁc systemic symptoms of a subacutenature, but eventually the patient followed a fulminantclinical course. What were the positive signs? What
were the positive ﬁndings on laboratory examinationand the condition on admission?
Mr. Inoue (6th-grade student): Laboratory ﬁndings
indicated the presence of anemia, and the patient had
mild consciousness disturbance, and mild hypertension.
Dr. Nagata: The clinical features were not so distinctive on admission, but after admission, the patientdeveloped severe resistant hypertension.
Mr. Inoue: Stool occult blood was positive, and urinalysis also revealed the presence of occult blood and
RBC.
Dr. Nagata: Urinalysis revealed not only an occult
blood reaction of the urine, but also RBC on microscopic examination. Microscopic hematuria is a signiﬁcant ﬁnding. Microscopic hematuria may occasionallybe observed even in healthy women, but in malepatients, hematuria is an important morbid ﬁnding. The
balloon of self-retaining catheters can damage the tissue of the urinary bladder. Can this possibility be considered in this patient? Was hematuria persistent?
Dr. Teramoto: The hematuria was persistent fromthe time of admission.
Dr. Nagata: There was microscopic but no macroscopic hematuria. Right?
Dr. Teramoto: Gross hematuria was not observed inthis patient until the terminal stage.

Keio J Med 2004; 53 (2): 103–114

Dr. Nagata: You mean hematuria was detected consistently whenever urinalysis was conducted?
Dr. Teramoto: Yes. The hematuria was not attributed to trauma associated with insertion of the selfretaining balloon catheter in the bladder.
Mr. Inoue: Urinalysis revealed G urinary protein.
Peripheral blood examination revealed a mean corpuscular volume (MCV) indicative of normocytic normochromic anemia. The serum FDP was elevated, indicating activation of the ﬁbrinolytic system.
Dr. Nagata: Did the patient have eosinophilia, Dr.
Teramoto?
Dr. Teramoto: The patient never had eosinophilia.
Dr. Nagata: Was the serum IgE measured?
Dr. Teramoto: No.
Dr. Nagata: How about other signiﬁcant ﬁndings in
the patient?
Mr. Inoue: There was elevation in the serum levels
of inﬂammatory markers, including and elevated ESR
and increase in the serum CRP level to 14.3 mg/dl.
Dr. Nagata: These are remarkable abnormal ﬁndings. The ESR was as high as 110 mm in the ﬁrst hour.
Mr. Inoue: The serum albumin and serum cholinesterase levels were decreased.
Dr. Nagata: These ﬁndings may be reﬂective of malnutrition.
Mr. Inoue: The serum iron level was low, while theserum ferritin level was high. The total iron-binding
capacity (TIBC) and the unsaturated iron-binding capacity (UIBC) were slightly low. These ﬁndings may besuggestive of chronic inﬂammation. Other laboratory
ﬁndings included an increase of the serum level of IgG,
decrease of the 50% hemolytic unit of complement(CH50), and increase of the serum level of VB12. In
addition, MPO-ANCA (P-A NCA was positive (þ), although this was not detected immediately after admission. These are all the signiﬁcant ﬁndings in this patient,
I suppose.
Dr. Nagata: Is the MPO-ANCA titer slightly high orvery high?
Dr. Teramoto: It is very high.
Dr. Nagata: It is very difﬁcult to make a diagnosis in
this patient, isn’t it? Such diverse clinical features andabnormal laboratory ﬁndings are observed. It is difﬁcult
to determine which features might be relevant andwhich can be ignored while making a diagnosis. At thetime when the patient was referred to the Department
of Internal Medicine, I suppose Dr. Teramoto thoughtthat the patient had a disease falling under the categoryof internal medicine rather than psychiatry. Positiveﬁndings, from which the presence of an organic diseasecan be distinctly suspected, namely, pyrexia and weight
loss, were also present. Should the differential diagnosis
include malignant tumor, collagen vascular diseases,
and infections? Many of the symptoms and ﬁndings

107

observed in this patient may occur in malignant tumors,collagen vascular diseases, as well as infections. Thus, it
is impossible to make a precise diagnosis based on theclinical ﬁndings alone.
Shall we now discuss the differential diagnosis of thispatient?
Dr. Teramoto: Gastroscopy and computed tomography (CT), conducted as screening tests for malignant
tumors, did not indicate the presence of any malignant
tumor.
Dr. Nagata: So, screening of the whole body bydiagnostic imaging and endoscopy revealed no tumor
or tumor-like lesions. We are conducting a diagnosis of
exclusion. How about infectious diseases?
Dr. Teramoto: The presence of an infectious disease
was repeatedly examined for by chest roentgenography
and bacterial culture.
Dr. Nagata: Do you mean that there was no positive evidence of infection as determined by bacterial on
cultures?
Dr. Teramoto: Yes, the bacterial cultures were all
negative.
Dr. Nagata: Then, the CSF and urine were examined. Was any inﬂammatory mass found on CT?
Dr. Teramoto: No, no inﬂammatory mass was found.
Dr. Nagata: At this time-point, consciousness disturbance was a prominent clinical feature. Clouding of
consciousness was observed, with a JCS score of I-3.
Dr. Teramoto: This score corresponds to the stage at
which simple responses to questions are possible.
Dr. Nagata: The vaccination against inﬂuenza weighs
on my mind here. Generally, this patient had no focal
neurological deﬁcit, but he had disturbance of consciousness. Dr. Abe, what diagnoses would you consider in such a case? Would you comment on whether
or not the patient had any neurological disease?
Dr. Abe: Since the patient’s speech could not be understood by others, it was very difﬁcult to evaluate theneurological ﬁndings. However, the patient’s eyes wereopen, and there were no laterality in spontaneous
movements.
The mild nuchal rigidity may also be attributable topoor general condition and contracture. Disturbanceof consciousness without any focal neurological deﬁcit
indicates diffuse disturbance of cerebral function, but it
can occur from various causes. The differential diagnosis in this patient was as follows: Meningoencephalitis;
slow virus infection, such as Creutzfeld-Jakob disease(CJD), and ADEM, when the subacute course is taken
into consideration; The other diagnoses that must be
considered include metabolic diseases, such as pulmonary encephalopathy, hypoxic encephalopathy, hepatic
encephalopathy, uremia, Wernicke encephalopathy,
and avitaminoses, e.g., pellagra, electrolyte imbalances,including hyponatremia, hypernatremia, and hyper-

108

calcemia, systemic diseases such as collagen vasculardiseases, vasculitis, and epilepsy.
There was some reference to malignancy. Limbic
encephalopathy as a remote association may be enumerated as a differential diagnosis in this context. Examination conducted at our department ruled out meningoencephalitis and ADEM.
In this context, one patient who developed ADEM
following prophylactic vaccination against inﬂuenza has
been reported.
Dr. Nagata: Could it be possible that the patient had
Guillain-Barré syndrome after the vaccination?
Dr. Abe: Yes, Guillain-Barré syndrome-like symptoms were present and the diagnosis could be considered, however, the patient also had disturbance of
consciousness, which is rather suggestive of a central
nervous system disorder rather than peripheral neuropathy.
Dr. Nagata: This syndrome can hardly be consideredin this patient, because motor neuropathy was absent.
Dr. Abe: This syndrome must be suspected if
decreased muscle strength of all the four extremities
occurs acutely. Central neuropathy indicates the presence of ADEM, or infection may also have been caused
by prophylactic vaccination, although the probability(for infection to be caused by vaccination) is considerably low. In any event, while it is very rare for
infections to be related to prophylactic vaccination, thepossibility was entirely ruled out by laboratory examination. Slow virus infection can hardly be considered in
the differential diagnosis, and hepatic encephalopathy
and pulmonary encephalopathy may be ruled out by theabsence of any abnormal laboratory ﬁndings.
Dr. Nagata: Since uremia was absent before admission, it is ruled out as the cause of the consciousness
disturbance in this patient. Vasculitis may still accountfor the patient’s condition. The possibility of malignant
tumor associated with the paraneoplastic syndrome islow, isn’t it? ADEM was suspected, but it was ruledout by imaging. The vaccination against inﬂuenza canhardly be regarded as being related to the patient’s
condition, right?
Ms. Ueda: While it remains unclear if the consciousness disturbance can be correlated with the othersymptoms, which included pyrexia and general malaise,
and with the laboratory ﬁndings, based on the laboratory ﬁndings and diagnostic ﬁndings, I consider vasculitis to be one of the differential diagnoses, based on
the presence of chronic inﬂammatory markers, anemia,
and elevated MPO-ANCA titers. Among these, druginduced vasculitis, e.g., microscopic polyangitis (MPN)
and Churg-Strauss syndrome, must be strongly considered in the differential diagnosiss.
Dr. Nagata: You consider the possibility of vasculitis
caused by drugs. That is why you asked about the

Nagata H, et al: A man with confusion, fever, and positive MPO-ANCA

details of the treatment received by this patient, is thatright?
Ms. Ueda: Yes.
Dr. Nagata: Mr. Iguchi, what made you wonder
about the presence or absence of purpura?
Mr. Iguchi: I suspected vasculitis too.
Dr. Nagata: Henoch-Schönlein purpura may also be
suspected.
Mr. Iguchi: Since weight loss and purpura are
included in the diagnostic criteria of vasculitis, I
assumed that the presence of these symptoms may be
useful pointers for making a diagnosis.
Dr. Nagata: In the present patient, it would appear
that it would have been terribly difﬁcult to make a
deﬁnitive diagnosis early after admission. Many differential diseases were enumerated, but the decisive diagnostic factor was considered to be the elevated titer of
MPO-ANCA. Perhaps, Dr. Teramoto also thoughtso, and he may have considered vasculitis syndrome asa disease associated with positivity for MPO-ANCA.
Now, among the diseases enumerated, Mr. Inoue,
which do you think would be characterized by positivity
for ANCA (Table 2) in vasculitis syndrome (Table 3)?
Mr. Inoue: I considered MPN. Positivity for MPOANCA is associated with MPN. It has been believedthat the antibody is rarely present in classic cases of PN.
Dr. Nagata: Wegener’s granulomatosis may be characterized by a positive test for ANCA?

Table 2

ANCA-associated Small-vessel Vasculitis

Wegener’s granulomatosis
Microscopic polyangitis
Churg-Strauss syndrome
Pauchi-immune renal-limited glomerulonephritis

Table 3
I.

Vasculitis Syndromes

Systemic necrotizing vasculitis
A. Polyarteritis nodosa (PAN)
1. Classical PAN
2. Microscopic polyangiitis
B. Allergic angitis and granulomatosis of Churg-Strauss
C. Polyangitis overlap syndrome
II. Wegener’s granulomatosis
III. Temporal arteritis
IV. Takayasu’s arteritis
V. Henoch-Schölein purpura
VI. Predominantly cutaneous vasculitis (hypersensitivity vasculitis)
A. Exogenous stimuli proven or suspected
1. Drug-induced vasculitis
2. Serum sickness and serum-sickness-like reactions
3. Vasculitis associated with infectious diseases
B. Endogenous antigens likely involved
VII. Other vasculitis syndromesKeio J Med 2004; 53 (2): 103–114

Mr. Inoue: No. This is a weak possibility, because
Wegener’s granulomatosis is characterized by CANCA
positivity.
Dr. Nagata: How about other types of vasculitis?
Ms. Ueda: In Churg-Strauss syndrome, the numberof eosinophils is usually believed to be increased. Thiscondition does not seem to match with the patient’s
condition, because no eosinophilia or asthmatic symptoms were observed.
As for the drug-induced types of vasculitis, the drugs
commonly known to cause this syndrome are propylthiouracil and hydralazine (hydrochloride). Since thepatient had no past history of medication with thesedrugs, this type of vasculitis was excluded from thediagnosis.
Dr. Nagata: Is it impossible to include HenochSchönlein purpura in the differential diagnosis?
Mr. Inokuchi: Henoch-Schönlein purpura wasincluded in the differential diagnosis. However, since
the serum test for MPO-ANCA was positive, we morestrongly considered the other two diseases mentioned
above, MPN and Churg-Strauss syndrome, in the differential diagnosis.
Dr. Nagata: You mean that classical PN need not be
considered in the differential diagnosis because the patient with classical MPN was MPO-ANCA positive?
Mr. Inokuchi: Yes. As MPO-ANCA is positive, classical PN is not included in the differential diagnosis.
Moreover, MPN rather than Chung-Strauss Syndromeis assumed to be more consistent with the absence ofasthmatic symptoms and eosinophilia in this patient.
Dr. Nagata: This 73-year-old man who had asubacute-fulminant course also had anemia and hypertension. Is this consistent with the diagnosis of MPN?
Mr. Inokuchi: Hypertension is caused by acute progressive glomerulonephritis (GN) associated with MPN.
MPN may also lead to gastrointestinal hemorrhage,
which could explain the occult blood positivity of thestools. Hematuria may also be associated with nephropathy in cases of MPN.
Dr. Nagata: Hematuria may be an important feature for making a diagnosis in this patient. Hematuria isassociated with GN.
Mr. Inokuchi: How about a renal biopsy in this patient? Was it conducted?
Dr. Nagata: Dr. Teramoto, please explain the diagnostic approach and the treatment administered to thispatient, including the indications for renal biopsy.
Dr. Teramoto: Yes, I shall explain the course of thepatient post-admission.
After the patient was referred to the Department of
Gastroenterology, the pyrexia persisted and the hypertension became severe and resistant to treatment. To
determine the cause of the fever of unknown origin andthe consciousness disturbance, the patient was exam-

109

ined by both a rheumatologist and a neurologist.
On January 2, the patient developed airway obstruction
because of secretions, and developed cardiorespiratoryarrest. A renal biopsy could not be performed becauseof the poor general condition of the patient. There wereno particular regions of angiitis that could be biopsied.
As for conﬁrmation of the diagnosis of vasculitis, thepatient was already intubated by the time this diagnosis
was considered, because the patient was found to bepositive for MPO-ANCA in early or mid-January. The
general condition of the patient did not permit any
invasive examination.
Dr. Nagata: If either of the testes had been enlarged,
it could have been biopsied. If skin rash had beenpresent, a skin biopsy might have been performed.
However, neither was observed, and the patient’s general condition did not allow any invasive examination to
conﬁrm the diagnosis of vasculitis.
Then, Dr. Suwa, could you comment on the important clinical signs in this case, the diagnostic approach
employed, and the treatment options?
Dr. Suwa: It was very difﬁcult to make a diagnosis in
this patient. Treatment was also difﬁcult and the clinicalcourse took an acute turn, resulting in death.
The most remarkable abnormalities in this patient,observed before he developed terminal respiratory andcirculatory failure, included pyrexia, neuropathy, hypertension, anemia, nephropathy (hematuria), highlevels of inﬂammatory markers (ESR 110 mm/h, CRP
14.30 mg/dl), hyper g-globulinemia, and high serum
titers of MPO-ANCA. A particularly noteworthy ﬁnding useful for making a precise diagnosis was the elevated serum MPO-ANCA titer to as high as 1,000
EU. The past history of arthralgia, myalgia, and testicular tumor must also be considered. The mostprobable differential diagnostic possibility that can onedimensionally explain the complicated morbid condition of the patient is MPO-ANCA-associated vasculitis.
Histopathological evidence of vasculitis would have
conﬁrmed the diagnosis of microscopic polyangitis.
However, in the absence of evidence of MPN, thepatient’s condition may be diagnosed as ANCAassociated vasculitis, including the pulmonary-renal
syndrome that leads to pulmonary hemorrhage andacute progressive GN.
An interesting issue that must be considered at thispoint is the relationship between drugs and infections.
For instance, some reports have shown that hydralazine
administration for hypertension can be associated withpositive ANCA positivity, and that proton pump inhibitors, i.e., remedies for peptic ulcers, may conversely
induce gastrointestinal hemorrhage. In the present case,however, the condition was not assumed to be drugrelated. Some studies have shown that MPO-ANCA is
produced in some cases of infections, e.g., hemolytic

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Nagata H, et al: A man with confusion, fever, and positive MPO-ANCA

Fig. 1 Kidney. Macroscopic ﬁndings (A cut was made at the hilum of
the kidney). It is deeply red on the whole.

Fig. 2 Kidney. A low magniﬁcation view. Mostly normal glomeruli
are also present, but crescent-forming glomeruli and hyalinized glomeruli are remarkable.

Fig. 3 A magniﬁed view of the glomeruli. Crescent formation isobserved.

Fig. 4 PAS staining of the kidney. Crescents formed along theBowman’s capsule stain pink and become distinct.

Fig. 5 PAM staining of the kidney. There is no marked change in thebasement membrane of the glomerular capillaries.

streptococcal infection, GN, and subacute endocarditis,
to induce vasculitis. We have also encountered a patientin whom the MPO-ANCA titer increased after the occurrence of hemolytic streptococcal infection and thepatient went on to have ANCA-associated vasculitis. In
the present patient, it is also possible that the vaccination against inﬂuenza caused some kind of imbalance ofcytokines, followed by a series of morbid events.
Dr. Nagata: What was the direct cause of death, Mr.
Chihiro Ito?
Mr. Ito (C.): The direct cause of death was assumed
to be renal failure or pulmonary hemorrhage.
Dr. Nagata: Pneumonia was also suspected from theradiographs. Was there an acute process that led todeath?
Dr. Teramoto: Two or three days before his death,the patient started having bloody sputum, and progressive deterioration of his respiratory status. Thus, pulmonary hemorrhage was assumed to have occurred
about two days prior to the patient’s death.

Keio J Med 2004; 53 (2): 103–114

Fig. 6 Lung. Macroscopic ﬁndings (A cut was made at the hilum of
the lung). The cut surface shows dark red.

Fig. 8 PAM staining of the lung. There is no marked change inbasement membrane of the pulmonary capillaries.

Dr. Nagata: Could you explain the histopathologicalﬁndings of this patient, Dr. Shibata?
Dr. Shibata: As we have just heard, various differential diagnostic possibilities were considered clinicallyin this patient. From the histopathological standpoint as
well, MPN was considered as the ﬁrst possibility, basedon the patient’s clinical course. However, a detailed
systemic histopathological screening did not reveal any
evidence of vasculitis. (Fig. 1)
Autopsy ﬁndings of the kidney are shown ﬁrst. Thisis a cut section of the kidney at the level of the hilum.
Macroscopically, the kidney appears slightly enlarged,
with a slightly congested appearance. (Fig. 2)This is a low-magniﬁcation view of the kidney. Itshows marked congestion. Most of the glomeruli
observed show hyalinization, and crescent formation
can also be visualized. These ﬁndings indicate a generally damaged kidney. (Fig. 3)
This is a highly magniﬁed view of the glomeruli. Socalled crescent formation is observed with abundant
cellular components adhering to the wall of Bowman’s

111

Fig. 7 Lung. A low magniﬁcation view. Alveolar hemorrhage is
generally remarkable.

capsule. Crescent formation is seen in approximately
80% of all the glomeruli. (Fig. 4)This is a slide showing the periodic acid Schiff (PAS)staining reaction. Crescents are seen along the wall of
Bowman’s capsule. In this region, the nuclei are mostly
lost, and a ﬁbrous crescent is formed. (Fig. 5)This is a slide showing the periodic acid methenamine silver (PAM) staining reaction. Crescents areseen along Bowman’s capsule. PAM staining is very
useful for examining whether or not some deposits
are present in the basement membrane. PAM staining
did not reveal thickening of the basement membrane of
the capillary vessels, duplication of the basement membrane, or any deposits on the basement membrane.
As we have seen, crescentic GN was present in
the kidney, but there was no evidence of vasculitis. No
deposits were conﬁrmed on the glomerular basement
membrane, either. We investigated whether or not immune complexes were present, although the data are
not shown in this presentation. There was no immune
complex deposition along the basement membrane.
(Fig. 6)
These are the autopsy ﬁndings of the lungs. Here is
the hilum of the left lung, along which a transverse
section was cut, and here is the right lung. The whole
lung looks red. Alveolar hemorrhage and congestion
and/or edema were clearly observed in the upper lobe.
(Fig. 7)This is a low-magniﬁcation view of the lung. In regard to the alveolar structure, they usually appear clear
because of intra-alveolar air. Unlike the normal structures, hemorrhage is widely observed in the alveoli andthere is no space for air. (Fig. 8)
Since the patient had alveolar hemorrhage, we
looked for the presence or absence of vasculitis-likechanges. This is a slide stained with PAM, showing
alveolar capillaries. In the presence of vasculitis, thebasement membrane of the alveolar wall capillaries

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Nagata H, et al: A man with confusion, fever, and positive MPO-ANCA

A low magniﬁcation view of normal cerebral cortex.

Fig. 10 A low magniﬁcation view of the cerebral cortex of this patient. The regions corresponding to 3–5 layers of cerebral nerve cells
show coagulative necrosis.

Fig. 11 A high magniﬁcation view of normal cerebral cortex. Nerve
cells are present.

Fig. 12 A high magniﬁcation view of the cerebral cortex of thispatient. Deﬁcits of medium to large nerve cells are observed.

Fig. 13 Normal cerebellum. Purkinje cells are present in areas bordering the molecular layer and granular layer.

Fig. 14 The cerebellum of this patient. Deﬁcits of Purkinje cells areobserved.

Fig. 9

Keio J Med 2004; 53 (2): 103–114
Table 4 Glomerular Diseases That Clinically Show Findings ofAcute Progressive GN and Histologically Accompany Crescent Formation
1. Primary glomerular disease (crescent-forming nephritis)
Type I: Anti-GBM disease [pulmonary hemorrhage ()]Type II: Immune complex type [anti-GBM (), ANCA ()]Type III: Pauci-immune type [ANCA (þ)]
2. Conditions accompanying systemic diseases
General vasculitis
Microscopic polyangiitis [ANCA (þ)]
Wegener’s granulomatosis [ANCA (þ)]
Churg-Strauss syndrome [ANCA (þ)]
Goodpasture disease [anti-GBM (þ), pulmonary hemorrhage(þ)]
SLE
Henoch-Schönlein purpura
3. Diseases accompanying infections
Acute poststreptococcal GN
Infective endocarditis
MRSA-related nephritis

often show distinct rupture or tears, but the alveolar
structures and the structure of the basement membraneof the alveolar capillaries is maintained. Thus, no evidence of vasculitis was conﬁrmed in the lungs either.
(Fig. 9)These are the ﬁndings of the brain. This is the surface of a normal cerebrum, which is densely packed
with nerve ﬁbers and (nerve) cells. (Fig. 10)
This is an image showing some vacuolar layers thatare present in the brain, as compared with the dense
packing with nerve ﬁbers and cells mentioned above.
(Fig. 11)This is a magniﬁed view of the normal cerebral cortex. Many pyramidal nerve cells are present, and there
are no vacuolar spaces. (Fig. 12)
In this patient, nerve cells are severely degenerated.
Histopathological examination revealed the presence oflaminar cortical necrosis, in which the cerebral cortex ispartially destroyed by coagulative necrosis. This ﬁnding
may be associated with the ischemic changes that might
have occurred when the patient had cardiopulmonaryarrest one month before his death. (Fig. 13)
This is the normal cerebellum, showing round Purkinje cells in areas bordering the granular layer and themolecular layer. (Fig. 14)
In this patient, no Purkinje cells were present in theboundary between the layers. This is also a change thatmight be associated with ischemia caused by the cardiopulmonary arrest that occurred approximately one
month before the patient’s death.
Only ischemic changes could be conﬁrmed on autopsy of the brain. That is as far as the tissue slides areconcerned. (Table 4)
For cases of acute progressive GN, histopathologically characterized by crescent formation, three main

113

etiological possibilities are considered; primary glomerular disease, changes associated with systemic diseases,
and changes associated with infectious diseases.
Primary glomerular disease is mainly classiﬁed into
three types, type I with anti-basement membrane antibody, type II caused by immune complex deposition,and type III which is positive for ANCA and has no
relation to immunoglobulin at all. Types I and II wereruled out in this case, because precipitation of immunoglobulins could not be conﬁrmed at all in any tissue
examined. The possibility of crescent-forming nephritis
associated with ANCA positivity was therefore considered.
Crescentic GN is known to be associated withsome systemic diseases. In connection with Goodpasture’s syndrome, however, no evidence of vasculitis
was observed in any tissue. As for the diagnosis ofWegener’s granulomatosis, no granulomas could be
conﬁrmed. In relation to Churg-Strauss syndrome,
granulomatous vasculitis could not be conﬁrmed. Antibasement membrane antibody was not detected in theserum. These diseases are therefore ruled out, because
they are hardly supported by the histological and clinical ﬁndings.
In relation to infectious diseases, GN following
hemolytic streptococcal infection, infectious endocarditis, and methicillin-resistant Staphylococcus aureus(MRSA)-related nephritis is associated with crescentformation. However, these conditions were ruled out
based on the clinical features.
So, the etiological diseases were, thus, the case washistopathologically diagnosed as a case of primary glomerular disease with crescent-forming MPO-ANCAassociated nephritis not related to immunoglobulin.
With that, I end my presentation.
Dr. Nagata: Thank you, Dr. Shibata.
Dr. Suwa: The present patient had severe anemia,with a Hb level of 7.3 g/dl, and the stool was positive(þþþ) for occult blood. From these ﬁndings, gastrointestinal hemorrhage was suspected. Was there any gastrointestinal lesion observed histopathologically thatwould warrant a special mention?
Dr. Shibata: There were no lesions that could lead togastrointestinal hemorrhage.
Dr. Kimura (Pathology): Is MPO-ANCA a pathogenic antibody, or an antibody that is merely elevatedin patients with the disease?
Dr. Suwa: I shall talk a little more about ANCA ﬁrst.
ANCA, i.e., anti-neutrophil cytoplasm antibody, isbrieﬂy classiﬁed into P-ANCA and C-ANCA, according to the pattern of staining of the cytoplasm. The
main antigen for P-ANCA, also abbreviated as MPOANCA, has been found to be myeloperoxidase. The
corresponding antigen for C-ANCA, also abbreviatedas PR 3-ANCA, observed in cases of Wegener’s gran-114

ulomatosis is proteinase 3. As for the etiological significance of MPO-ANCA, MPO-ANCA is produced byimmunization or (external) injection of antibodies tosecondarily induce vasculitis in animal experiments.
These experiments are based on the following hypothesis: neutrophils and endothelial cells, which are activated by inﬂammatory cytokines, adhere to each other;
ANCA acts on the adhering cells to release MPO andPR 3 granules, which cause histological changes. Thishypothesis is called the ‘‘ANCA cytokine sequence
theory’’. Furthermore, from the fact that the ANCA
titer varies in parallel with the clinical disease activity,

Nagata H, et al: A man with confusion, fever, and positive MPO-ANCA

it is assumed that ANCA may directly participate intissue damage in a way similar to anti-DNA antibodies
and anti-phospholipid antibodies in SLE. Thus, strong
etiological signiﬁcance is attached to ANCA, but further study is required.
Mr. Iguchi: I wonder why the reticulocyte count was
not increased despite the presence of severe anemia.
What were the bone marrow ﬁndings?
Dr. Shibata: The bone marrow showed slight hypoplasia at autopsy, but there were no distinctive ﬁndings.
Dr. Nagata: I shall now declare the CPC closed.
Thank you very much for your participation.