Giant cell arteritis - do not ignore the obvious

 Dear Colleagues

I was presented an elderly woman who had a three week history of illness which included:

1) Bitemporal headache; worse when touching the scalp.

2) Jaw claudication; she could not initially open her mouth.

3) Non-productive cough

4) Change in her voice 

5) Fever of 37-38ºC

6) Weight loss of 3 kg

7) Fatigue

She had been vaccinated against COVID-19 and had received a second ‘shot’ prior to the onset of symptoms. 

On further questioning, the patient admitted to right neck pain and photophobia. She did not complain of stiff of the neck or skin rash.

There were no other respiratory symptoms. There was no history of tuberculosis exposure or infection.

Past medical and surgical history included hypertension, left lung cancer (open lobectomy only; no chemoradiation), constipation and appendicectomy as a child. 

The patient was using amlodipine 5 mg once daily, senna and magnesium oxide. There were no known drug allergies. 

The patient was a ‘never smoker’ and was not a regular or prior heavier consumer of ethanol. 

Physical examination revealed a pseudo-normalisation of blood pressure at 107/65. Other vital signs were stable.

Hands: Normal

Arms: Proximal muscle wasting and sagging skin beneath the triceps muscle suggestive of muscle loss.

HEENT: No conjunctival pallor or jaundice. Teeth - multiple treated caries. No current dental caries. Jaw opened normally; no trismus present. No intra-oral swelling. Temporal artery tenderness was present.

CVS: JVP not elevated Apex: Heaves/thrills Heart sounds I & II: 3rd / 4th heart sounds (-), gallop rhythm (-) Rub (-) Peripheral pulses all present and normal. No clinical signs of DVT.

RESP: Trachea central and no tug sign. Left lateral thoracotomy scar. Chest tube insertion scar beneath the above scar. Percussion: Normal. Auscultation: No added sounds. 

ABDO: Soft, non-distended, tenderness in the epigastrium in the area overlying the lower abdominal aorta. No guarding, hepatosplenomegaly, masses, or ascites. Rectal exam: not performed.

NEURO: Revealed no evidence of neck stiffness, Jolt sign or Kernig sign. There were no cerebellar signs. Power was normal. Romberg sign was negative. Walking revealed a normal gait.

Clinical Impression

• Post-vaccination adverse reaction

• Viral / bacterial infection e.g. chest infection, meningitis, COVID-19 infection, etc  

• Giant cell arteritis

• Meningitis

Data Review

Chest radiograph revealed a raised left hemidiaphragm consistent with previous lung surgery for malignancy.

Electrocardiogram was within normal limits.

Laboratory data revealed an anemia of chronic disease. C-reactive protein was 22 and erythrocyte sedimentation rate was 112 mm/hr. Autoantibodies were negative. 

Blood cultures were negative x 2. 

COVID-19 test was negative x 2.

A lumbar puncture was not performed. 

Head computed tomography was within normal limits for the patient’s age.

Ultrasound scan of the temporal arteries did not reveal any abnormality.

Slit lamp examination did not reveal retinal changes.

Likely Diagnosis

It was considered by the team that the patient had some form of viral infection or a vaccine related reaction.

It was decided to observe the patient without any treatment. The patient C-reactive protein decreased spontaneously to half the original value but the low-grade fever still persisted. She still experienced persistent bitemporal headache.

My impression

There is a medical saying from Western medical teaching that does not appear in the Japanese medical vernacular, which is “until proved otherwise”.

This means that in this case, the patient has giant cell arteritis until proved otherwise, or in other words, until it can be DISPROVED. That’s right, although one has to do tests to confirm the diagnosis, the patient is assumed to have the diagnosis until it can be disproved. 

The constellation of symptoms and signs is strongly supportive of giant cell arteritis including a non-productive cough and change in voice. 

As a word of warning, giant cell arteritis can wax and wain, but it usually does not disappear spontaneously. Symptoms can improve on occasion and then worsen. Hence, an improvement of the patient’s condition should not give the physician a sense of security. It is a false hope.

Hence, patients STILL need to 1) receive corticosteroid treatment [GCA is a MEDICAL EMERGENCY!] before a biopsy, unless a biopsy can be performed rapidly 2) undergo biopsy of the temporal artery (sometimes bilaterally) to confirm the diagnosis. Biopsy is still possible and changes are still present several weeks after starting corticosteroids; this is usually ample time to organise a biopsy. 

In this case, a PET-CT scan might also have been helpful to reveal inflammation of the aorta.

COVID-19 

Performing a literature search with respect to giant cell arteritis and COVID-19 there is a small body of growing evidence that suggests that COVID-19 itself can initiate GCA. The number of cases of GCA has risen during the pandemic. As COVID-19 directly affects blood vessels through it’s attachment to the ACE-2 receptors, the logical next step would not be surprising that it might initiate inflammation of arteries.

In view of the catastrophic outcomes of GCA which include blindness and stroke, such a diagnosis cannot simply be observed without treatment or further tests.

Whether the COVID-19 vaccine itself is an initiator of GCA does not seem to be supported in the literature at this time. 

Remember though, the above patient COULD have still become infected with COVID-19 despite vaccination. PCR tests can be falsely negative. 

It takes several weeks after a vaccine is given for protective antibodies and T-cells to be generated. Even then, a second booster is just that! It is a booster because the first vaccine was not enough to provide thorough protection. Hence, it is possible that the above patient became infected with COVID-19 and manifested a milder form of infection, but one that still initiated GCA. This is purely hypothetical of course, but it could explain the above scenario. 

Take Home Message

If it looks like a duck, if it walks like a duck and if it quacks like a duck, then it’s a duck! The same is true of giant cell arteritis. Do not ignore it and hope it will go away. 

Think in terms of ‘until proved otherwise’ for the serious life threatening diagnoses / medical emergencies.  In such situations, it is better to over investigate and over treat because if present, the patient will be saved. In some cases it will not show the diagnosis, but the patient will come to no significant harm. In view that there is no serum marker of the diagnosis of giant cell arteritis, invasive tests are required when non-invasive one are unrevealing. Even then biopsy may look normal because of skip lesions. Be warned and be ready to treat even if results cannot confirm the diagnosis. 

A diagnosis is not based solely on a test. It is based on a constellation of symptoms and signs which may include supportive tests. In some cases, the physician just has to do what is appropriate even when a test comes back negative but the clinical pattern is consistent with the diagnosis. 

Being a physician is not easy and absence of a test should not be a barrier to making a diagnosis or to treating. 

A does not always equal B

Dear Colleagues

I was recently presented an elderly man with a longstanding history of rheumatoid arthritis, who presented with an acute onset of fever followed by a cough with sputum. 

History

The patient experienced a fever of 38ºC with associated sweats. There were no chills or rigors. 

The cough was productive of some sputum, albeit limited in quantity and frequency. There was no chest pain or dyspnea. 

The patient complained of posterior neck pain, but this was not a new symptom having been present for over 1 year. 

The patient lived with two other family members, but they were well. There were no new medications commenced in recent months. 

The patient’s rheumatoid arthritis was poorly controlled over the last 30 years leading to severe deformity of his hands and significant disability. However, he said that his symptoms were not worse recently.

He underwent total knee arthroplasties a decade ago for osteoarthritis of his knees. 

The patient was using methotrexate 4 mg once per week, folic acid 5 mg once per week, bucillamine, and tacrolimus 0.5 mg daily, respectively. 

The patient was a non-smoker, but he had been exposed to passive smoking over several decades years, working alongside his family members. He did not consume ethanol. 

The patient was initially seen at another hospital. There was no description of any physical examination having been undertaken there. However, notably his chest computed tomography scan showed infiltration in a crazy paving pattern, and his laboratory data showed an elevation of beta-D-glucan.

As a result, he was diagnosed with pneumocystis pneumonia secondary to immunosuppression. No confirmatory tests were performed. Sulfamethoxazole-trimethoprim was started as blind treatment.

Physical examination

On physical examination his vital signs were stable except for moderate hypertension. 

The patient was frail and emaciated, but not in acute distress.

HEENT: Normocephalic and atraumatic. Eyes - slight conjunctival pallor. No jaundice. Ear - normal. Nose - normal. Throat - missing many teeth; no active dental caries. Mild oral candidiasis (prior examination showed more extensive colonisation).

Cardiovascular examination: JVP: not elevated. Apex: No heaves/thrills. Heart sounds I & II: Distant. No 3rd / 4th heart sounds. No gallop rhythm, or rub. II/VI Levine ejection systolic murmur at the left parasternal border. No radiation to the carotid areas. Peripheral pulses all present and normal. No clinical signs of deep vein thrombosis.

Respiratory examination: Barrel shaped chest. Trachea central and shortened. Use of accessory respiratory muscles. Percussion: Hyper-resonant. Auscultation: Fine crackles in the mid left posterior chest with bronchial breathing and egophony. Otherwise, reduced breath sounds throughout. No high or low pithed wheezes.

Abdominal examination: No scars or hernial orifices. Soft, non-tender, non-distended. The liver could be palpated 1 cm below the costal margin and was non-tender. The spleen was impalpable. Percussion confirmed the above findings. The scratch test identified the liver to be spanning the epigastric area. Bowel sounds were normal. There was no costovertebral angle tenderness.

Rheumatological examination: 

HANDS - severe changes; ulnar deviation with subluxation at the MCPs. Mixture of boutonierre and swan neck changes in the digits. Z-deformity of the thumbs. There was no synovial swelling or increased temperature of the affected joints. 

ELBOWS: Preserved range of motion and no synovial swelling.

SHOULDERS: Muscle wasting around the joints. Destruction of the glenohumoral joints. No swelling or increased temperature. Able to lift his arms up to his head in the anteroposterior plane.

HIPS - Normal ROM.

KNEES - Evidence of bilateral knee replacements; increased temperature at the right lower knee joint area. No pain or tenderness.

ANKLES - Reduced ROM; no-tender and no increased temperature.

FEET - Claw toes.

DATA

Laboratory data did not reveal specific findings, except for a mild anemia, mildly elevated liver enzymes and renal dysfunction. 

Beta-D-glucan and D-Dimer were elevated.

The chest radiograph showed only hyperinflation, but no infiltrations.

The electrocardiogram showed non-specific findings such as p-mitrale and incomplete right bundle branch block. 

Chest computed tomography revealed a crazy paving pattern of interstitial changes.

IMPRESSION

It was considered that the patient had pneumocystis pneumonia based on the risk factors of immunosuppression, elevated beta-D-glucan and a consistent computed tomography pattern.

The patient was commenced on sulfamethoxazole and trimethoprim.

No induced sputa were examined and no bronchoscopy was performed.

ANOTHER LOOK!

Although the diagnosis may be correct here, it is by no means a certainty. Let’s reconsider the history. A typical diagnosis of pneumocystis pneumonia consists of many weeks of low grade fever, a non-productive cough and dyspnea, all of which are progressive. This patient had an acute presentation, making it more likely to be another diagnosis such as a viral or bacterial infection.

The beta-D-glucan elevation could have been due to the oral candidiasis in this case. Even mucosal colonisation can lead to elevated levels. The elevated levels indicate that there is a problem with a fungus, but it does not always equal pneumocystis pneumonia. 

To establish the diagnosis of pneumocystis pneumonia, it is usually recommended to obtain induced sputum or to perform a bronchoscopy with bronchoalvealoar lavage. The samples need to be stained for Pneumocystis jiroveci and/or a PCR test should be performed for the diagnosis.  

However, when it is difficult to obtain samples e.g. unstable C-spine, such as in chronic rheumatoid arthritis, the diagnosis can be inferred from the clinical picture. NOTE: there is an increased risk of an odontoid fracture in the cervical spine with neck manipulation in patients with long-standing rheumatoid arthritis.

In this case there are several other differential diagnoses which are related to the computed tomography crazy paving pattern which include:

- pulmonary embolism 

- tuberculosis 

- bacterial pneumonia (common), including mycoplasma

- acute interstitial pneumonia

- Goodpasture disease 

- drug-induced (bucillamine and methotrexate can cause interstitial pneumonia)

- lymphoma (note: tacrolimus is associated with lymphoma)

- sarcoidosis

The most compatible diagnoses associated with a rapid onset of symptoms are bacterial pneumonia or pulmonary embolism. 

The above list is not exhaustive, but it demonstrates that one needs to consider several diagnoses instead of jumping at one diagnosis. Confirmatory testing is the key. This means that A does not always equal B in terms of a computed tomography pattern equally one diagnosis.

In this case the bucillamine was stopped by chance because of the abnormal renal function. This drug could have been the cause or contributed towards the symptoms. Bucillamine is a very old rheumatology drug and this is no longer prescribed in modern day practice. 

The methotrexate was also prescribed at low dose (4 mg per week), which suggests that the management was not by a rheumatologist, but more likely via an orthopedic service. Note: In Japan, many rheumatology patients are managed by orthopedics because of the lack of trained rheumatologists. 

Moreover, UpToDate suggests that 1 mg folic acid is given DAILY, not weekly. Even giving folic acid on the same day as the methotrexate does NOT affect the drug’s efficacy. So this case reflects old practice and not current recommendations. 

TAKE HOME MESSAGES

• Never be satisfied with a brief history and physical examination. When dealing with a complicated history, especially past medical history and medications, one needs to take time to establish all the facts. 
• Medication can cause side effects!!! Could these be contributing to the patient presentation?
• Examine the patient carefully and completely. Do not take a few mins for such a complex patient. Take as much time as is necessary to understand them.
• When it comes to imaging studies, make sure you know the differential diagnosis of particular features. Even better still, obtain a formal radiological report rather than attempting to be a pseudo-radiologist. Please be aware that in many countries, doctors are do not report their own imaging. They always obtain the formal report of a radiologist; that includes chest radiographs as well! 

 

 

 

 

Think, think, think!

Dear Colleagues

It never ceases to amaze me how some physicians are unwilling to accept a different opinion. 

I was recently presented a patient in his 70s with a recent onset of fever and cough. 

He was a known heavy smoker of some 50 years. 

He denied contact with unwell persons, onsen/sento visits, contact with pets or previous tuberculosis exposure. 

His history was remarkable for atrial fibrillation treated by ablation, congestive heart failure and chronic low back pain. 

His medications included relatively standard treatments such as a beta-blocker, a loop diuretic, an aldosterone antagonist, a calcium channel anti arrhythmic agent, a direct oral anticoagulant, a non-steroidal anti-inflammatory drug, and a proton pump inhibitor. 

I was informed that his physical examination was normal except for some fine lung crackles and digital clubbing. 

A tentative diagnosis of an infective exacerbation of interstitial pneumonia was made and the patient was commenced on a penicillin derived antibiotic and corticosteroids. 

An antibody screen revealed elevated sIL-2 receptor, KL-6 and SPD. 

However, this was an over simplification. When I reviewed the case, the patient had been commenced on azithromycin by another hospital prior to admission to the current hospital. 

Two prior chest computed tomography scans had not been reviewed by a radiologist. There was upper lobe posterior calcification that suggested post-primary tuberculosis. 

Only one sputum examination was performed when THREE consecutive tests were required to check for acid-fast bacilli. 

No interferon gamma release assay had been performed for quiescent tuberculosis. 

When reviewing the patient (N95 masks were worn) he admitted to night sweats and 5 kg of weight loss prior to admission. 

Moreover, on detailing his smoking habit, he switched to e-cigarettes 5 years ago. He had recently switched to a new brand around the time of developing his current symptoms. 

This may not seem important, but there is a phenomenon called e-vaping associated lung injury (EVALI) which is due to the e-cigarette containing vitamin E. The vitamin E is sometimes included in some e-cigarette formulations. 

Imaging of EVALI via computed tomography shows several patterns and it is therefore not possible to exclude this as a cause by imaging alone. The history is perhaps the most important indicator. 

His physical examination was not normal at all. He had profound signs of chronic obstructive pulmonary disease including a barrel chest, a short trachea, hypertrophied sternocleidomastoid muscles and intercostal recession on inspiration. There were some mild scattered fine crackles. There was no evidence to suggest digital clubbing. 

“Atypical” pneumonia had not been considered either. Hence, tests for Legionella, Chlamydophila or Mycoplasma had not been performed. 

Hence, atypical pneumonia, EVALI, and post-primary tuberculosis (with possible reactivation) should have been on the differential diagnosis list. 

When suggesting such additional disorders I was smirked at, as if it was not possible. This was by a junior doctor no less. 

As a word of advice, never have early closure for a diagnosis. Never anchor to it when other information may suggest an alternative diagnosis. 

As new information becomes available, it opens up new possibilities, perhaps never once considered. 

Moreover, when there is a possibility of tuberculosis, further evaluations are warranted because if corticosteroids are indiscriminately used it could lead to reactivation and a disastrous outcome. Notwithstanding this, indiscriminate use of macrolide antibiotics can partially treat tuberculosis leading to negative smears and cultures. Be warned. 

It’s time for physicians to take the history and physical examination seriously. Ignoring it at the over-reliance of imaging and non-specific lab data will lead the physician down the wrong diagnostic alleyway.

Soluble IL-2 receptor can be found in diseases such a lymphoma, sarcoidosis, tuberculosis, many solid cancers and in autoimmune diseases. 

KL-6 is a marker for lung cancer developed in Japan. It is elevated in numerous diseases including interstitial pneumonia, sarcoidosis, tuberculosis, diabetes mellitus, allergic alveolitis, drug-induced pneumonitis, cryptogenic organising pneumonia, atypical pneumonia and so on. It is not specific to interstitial pneumonia alone. 

These kinds of tests have been hijacked and many junior doctors consider that elevation of a particular marker equals one disease like a shortcut for the diagnosis. It does not mean that at all.

Although such tests may suggest particular diseases, they are by no means diagnostic. 

As physicians, we need fine tune the diagnosis by focused history, physical examination and tests that provide a definitive diagnosis. 

Whenever tuberculosis is considered be warned about rushing in with corticosteroids. 

Think, think and think again.

There are less than two weeks before the next Dr. Branch’s Clinical Cases in Pharmacology. Please check out the current schedule below. 

http://jamep.or.jp/bccip

A new day

Dear Readers

I would like to welcome you all to this new medical blog where I will share anonymised information for the purposes of medical education. 

I do hope you will join me here when time permits.

Have a great day!

JB @ Dr. Branch’s Bedside BootCamp