Week Six - Case One Flashcards
(162 cards)
1
Q
what are 95% of lung cancer
A
carcinoma of the bronchus
2
Q
what are 2%
A
alveolar tumours
3
Q
when does death normally occur
A
after 30 ‘cell doublings’ of malignant cells
4
Q
what cancers can you get lung secondaries from
A
Breast
Kidney
Uterus
Ovary
Testes
thyroid
5
Q
what is the one year survival rate
A
20%
6
Q
what is the 5 year survival rate
A
5%
7
Q
what is the most common type of cancer worldwide
A
lung cancer
8
Q
how many deaths a year in the UK are due to lung cancer
A
32,000
9
Q
what is the male to female ratio
A
3:1
10
Q
it is the ‘what’ most common death in the UK
A
it is the third most common death in the UK
11
Q
what percentage of lung cancer cases does smoking cause
A
90%
12
Q
what is the worst type of asbestos
A
there are three colours, white blue and brown
blue is the worst - you are only at risk when the asbestos is broken up - as this releases the fibres
13
Q
what is the specific type of cancer asbestos produced
A
mesothelioma
14
Q
what are the other causes of lung cancer
A
Living in an urban, as opposed to a rural area
Passive smoking increases the risk 1.5x
Asbestos
There are three colours of asbestos – white, blue and brown – blue is the worst! You are only at risk when the asbestos is broken up – as this releases the fibres. It usually causes a specific type of tumour – mesothelioma.
Arsenic (in batteries and paints and fertilizer)
Iron oxide
Chromium
Petroleum products
Oil
Coal mining – this link is controversial – it is not actually the coal, it is the haemotite (iron ore) and silica that causes the cancer. Evidence is controversial – some coal mining areas have a higher incidence than the general population, whilst other areas don’t.
Radiation
Radon
Scarring – e.g. post TB
15
Q
what type of tumours tend to be associated with occupational factors
A
adenocarcinomas
16
Q
what are the four types of bronchial carcinoma
A
small cell
adenoma
squamous cell carcinoma
large cell
17
Q
what is the
- aetiology
- development time
- survival
- common location
of small cell carcinoma
A
- 20-30% of cases
- development time is 3 years- doubles in 30 days
- survival rate is around 5%
- found around the hilum/central of lung
18
Q
what is the
- aetiology
- development time
- common location
of adenoma
A
- 30% of cases
- development time is 15 years - doubles in 200 days
- most often found peripherally - therefore present late because they are less likely to cause obstruction symptoms
19
Q
what is the
- aetiology
- development time
of sqamous cell carcinoma
A
- 35% of all cases
- 8 years development time
20
Q
what is the
- aetiology
- common location
of large cell carcinoma
A
- 15% of cases
- presents centrally
21
Q
why do tumours arising in the main bronchus tend to present earlier than those arising in the small bronchus
A
because they will cause far greater symptoms at an early stage
22
Q
what percentage of tumours are in the lobar bronchi
A
80%
23
Q
how is squamous cell carcinoma usually present
A
as obstructive lesions of the bronchus leading to infection
24
Q
what can squamous cell carcinoma sometimes do
A
cavitates
this will occur when the central part of the tumour undergoes necorisis
25
what does lung cancer usually cause
hypercalcaemia
by bone destruction or production of PTH analogues
26
where do adenocarcinomas arise from
mucous cells in the bronchial epithelium
27
where do adenocarcinomas commonly invade
the mediastinal lymph nodes and the pleura, and spreads to the brain and bones
28
do adenocarcinomas usually cavitate
no
29
what can adenocarcinomas cause
excessive mucous secretion
30
what are large cell carcinomas `
basically just less well differentiated versions of adenocarcinomas and squamous cell carcinoma
31
what do large cell carcinomas do early on
metastatise early and therefore are associated with poor prognosis
32
what are bronchoalveolar cell carcinomas
very rare
a variation of adenocarcinoma
account for 1-2% of all lung carcinoma
33
how will bronchoalveolar cell carcinomas present
as a single nodule, or many small nodular lesions
34
what do bronchoalveolar cell carcinomas cause are major symptom
occasionally they cause production of huge amounts of mucous (which will be coughed up as sputum)
may appear like consolidation on the CXR
Causes ‘bronchorrhoea’ – diarrhoea of the bronchus – produces huge amounts of white sputum!
35
what do small cell carcinomas arise from and what is their nickname
arise from endocrine cells (Kulchitsky cells)
oat cell carcinomas
36
what type of cells are Kulchitsky cells
APUD cells, and as a result, there tumours will secrete many poly-peptides
37
what will some of these polypeptides do
cause auto-feedback to induce further cell growth
they can also cause various presentations such as Addison's and Cushing's disease
38
what do small cell carcinomas respond to and what is the prognosis
they respond to chemotherapy but prognosis is generally poor
they spread very early, and almost always inoperable at presentation
39
what are the two types of APUD cells
Open – secrete products in response to luminal contents, as well as nervous and hormonal stimuli
Closed – have no luminal receptors, and just respond to nervous and hormonal stimuli.
40
what are tumours of the apex of the lung called
superior sulcus tumours
41
what can superior sulcus tumours cause
severe pain - can affect the lower part of the brachial plexus - C8,T1 and T2
42
where will this cause severe pain
in the shoulder and down the inner surface of the arm
43
what is Pancoast's tumour
They can also spread to the chest wall, damaging the intercostal nerves, or even the brachial plexus and causing severe pain. This is caused by tumours in the apex of the lung (called superior sulcus tumours), and they can affect the lower part of the brachial plexus – C8, T1 and T2 – and this will cause severe pain in the shoulder and down the inner surface of the arm. There is also weakness of the hand. This is known as Pancoast’s tumour.
And the pain this causes is known as pancoast’s syndrome.
44
what can this lead to the loss of
the first rib - the tumour eats it up
45
what is any atypical tumour
Pancoast's tumour
46
what may also be involved and if it is - what can it result in
the sympathetic ganglion may also be involved
if this is damaged it can result in Horner's syndrome
47
what is Horner's syndrome
it results from damage to the sympathetic nervous system. in this particular case, it results from damage to the sympathetic chain at or above the stellate ganglion
48
where are these ganglion and therefore what type of tumour would have to cause this
these ganglia lie on the outside of the thoracic vertebrae, so it would have to be a central posterior tumour that would cause this
49
what are the clinical features of Horner's syndromw
Clinical features of Horner’s Syndrome include a drooping eyelid (ptosis) resulting from improper innervation of the superior tarsal muscle, ‘upside-down’ ptosis, miosis (constricted pupil) and dilation lag.
There may also be anhydrosis (decreased sweating) and enophthalmosis (an impression that the eye has sunk in) on the affected side of the face. There may also be dilation of blood vessels on the affected side, resulting in flushing, and a blood shot eye.
50
what can the primary tumour or lymph nodes do
metastasise and spread to the mediastinum and invade or compress the heart, oesophagus, superior vena cava, trachea, and phrenic or left recurrent laryngeal nerves
51
what does compression of the SVC cause
early morning headache, oedema of the upper limbs, facial congestion and distension of the jugular vein and veins on the chest
52
what may be affected with nodal presentation
supraclavicular and mediastinal lymph nodes can be affected
53
where are the normal blood borne mets
Blood borne – mets to the liver, bone adrenal glands, skin and brain. Mets in the brain can cause change in personality, epilepsy, or a focal neurological lesion. The deposits in the adrenal glands are rarely symptomatic, but often found on post mortem.
54
what is the ADH manifestations of bronchial carcinoma
inappropriate ADH secretion
this causes hyponatraemia - by denying the patient fluids, you can bring the fluid back to normal
55
what does ectopic ACTH secretion cause
Cushing's syndrome, will produce symptoms similar to those on steriods, and these patients (unlike those on steroids) will be very heavily pigmented
56
what is hypercalcaemia in bronchial carcinoma usually due to
the secretion of PTH (parathyroid hormone related peptides) This mostly occurs with squamous cell cancer
57
what are endocrine disturbances typically associated with
small cell carcinoma
58
what is the definition of paraneoplastic syndromes
non-endocrine, non-metastatic complication
these can be present several years before the tumour itself presents
59
what the neurological complications (2-16%)
Polyneuropathy – caused by antibodies against the myelin sheath – the damage is irreversible. It can present with virtually any neurological symptom.
Cerebellar degeneration – and other encephalopathies.
Lambert-Eaton Syndrome – essentially myasthenia gravis secondary to lung carcinoma. Other muscular condition may also occur.
60
what are the vascular and haematological complications
Thrombophlebitis migrans
Anaemia – can be microcytic or normocytic
61
what is HPOA
hypertrophic pulmonary osteoarthropathy
this occurs in 3% of cases (mostly small cell and adenoma). There will be joint stiffness, and severe pain in the wrists and ankles, sometimes also gynaecomastia. On x-ray there will be proliferative periostitis at the ends of the long bones, which have an ‘onion skin’ appearance. This is also associated with finger clubbing where cancer is the cause. It is thought to be caused by a blood borne factor released by the tumour – when patients have the primary tumour removed the pain goes away!
62
what is finger clubbing caused by and what is it the result of
caused by non-small cell carcinoma
this is thought to be a result of ecptopic hormone production which occurs in approx . 10% of cases
63
what does carcinoid syndrome present with and how is it diagnosed
Carcinoid syndrome – This presents with hepatomegaly, flushing and diahrroea – Diagnosed using 24 hour urine 5-HIAA tests.
64
what is the frequency of the symptoms present in bronchial carcinoma
Cough 41
Chest Pain 22
Cough and pain 15
Coughing blood (haemoptysis) 7
Chest infection <5
Malaise <5
Weight loss <5
Shortness of breath <5
Hoarseness <5
Distant spread <5
No symptoms <5
65
what do many patients have
co-existing COPD
66
what is the type of pain patients feel
fullness in the chest - later it may develop to a severe persistent pain
67
what is usually the earlier symptom
cough
68
what is common with tumours arising in the central bronchi
haemoptysis is common
occasionally these tumours may invade large blood vessels which can cause a massive haemopysis that can be fatal
69
what type of pneumonia is telling of bronchial carcinoma
Pneumonia – if this is recurrent at the same site, or is slow to respond to treatment, then this is suggestive of bronchial carcinoma. Tumours the block the bronchi prevent the proper functioning of the mucociliary escalator, and thus bacteria are retained behind the blockage.
70
when is stridor present
when there is an obstruction above the main carina
71
what is a monophonic and polyphonic wheeze
monophonic wheeze indicates there is only one obstruction - this is an ominous sign as the most probable cause is carcinoma
polyphonic wheeze is more suggestive of many airway blockages
72
what does hoarseness of the voice suggest
that there is left laryngeal involvement, particularly if there is also a bovine cough
if this involvement is present, then the tumour is inoperable
73
what are the ten natures of presentations
Typically, respiratory symptoms that do not respond to other standard treatments (e.g. cough that doesn’t respond to antibiotics)
Persistent symptoms
Change in nature of chronic ‘smoker’s cough’
History of smoking!
Isolated incidences of haemoptysis
Weight loss
Decreased appetite – as a result of the inflammatory reaction that the tumour induces – particularly TNF that is released
HPOA
Hoarseness of voice – involvement of the vocal chords of left recurrent laryngeal nerves
Pancoasts’ tumour
74
what does a physical examination show
usually normal, unless there is a significant bronchial obstruction or the tumour has spread
75
what would absent lung sounds and dullness to percussion at the lung bases suggest
phrenic involvement - as this will cause unilateral raising of the diaphragm
76
what type of tumours will be visible on X ray
symptomatic tumours
77
when can asymptomatic tumours be seen on X ray
when they are greater than 1cm in diameter
78
when will tumours confined to the central airways be visible
on bronchoscopy and CT
79
what percentage of lung cancers present with a mass
70%
virtually all small cell carcinomas and squamous cells will present as a visible mass
adenocarcinomas tend to occur more around the periphery of the lung than other regions
80
what can bronchial carcinoma appear as
Bronchial carcinoma can appear as a round shadow on an x-ray. It typically has a jagged edge, although this may not be distinguishable. It may also appear as a cavity.
81
what does bronchial carinoma spread to the lymphatic channels cause
This causes lymphangitis carcinomatosa which will cause dyspnoea and may causing a streaky shadowing on the x-ray. This is usually unilateral. If it is bilateral that it is more likely to be due to lung mets from other primaries, usually one from below the diaphragm, e.g. in the stomach or colon.
82
what is CT useful for q
looking for disease in the mediastinum and can also detect masses that are too small to be seen on CXR <1cm diameter
83
what is PET useful for
staging
84
what are the points with PET scanning
It is also useful for staging – where the f-deoxyglucose PET scan is employed.
No point in doing a PET if you don’t plan to operate! Basically it just tells you if it has spread – thus if it is suitable for surgery.
You would normally do a staging CT first – if this is clear, then you use a PET to look for more distant spread. If it all looks clear, then you can operate.
This is about 90% accurate for mets
On the PET results you look at the SUV value – the higher this is, the more likely the lesion is to be metastatic spread (scale is about 1-9)
85
what is bronchoscopy most useful to obtain
cytology and biopsy. Tumours that involve the first 2cm on either main bronchus are inoperable.
86
what may you also see on bronchoscopy
Widening of the angle of the carina – this suggests involvement of the mediastinal lymph nodes; either due to metastasis or they may be reactive. You can biopsy them on bronchoscopy by passing a needle through the bronchial wall.
Cytology – this is the study of cells that are no longer in their natural environmental structure – e.g. cell obtained from a bronchial washing. Histology is the study of both the cells, and the natural structure in which they are found.
Only really useful for tumours in an area about 10cm square around the hilum:
87
what is percutaneous aspiration and biopsy - CT guided biopsy
This is useful for peripheral lesions that cannot be seen by bronchoscopy. It is done through the chest wall and usually guided by x-ray or CT.
This is able to reach 75% of peripheral lesions that cannot be reached by bronchoscopy.
The chance of pneumothorax is very high (anywhere between 1-25% – thus the patient has to be fit enough to survive one of these if you are going to do this on them. Twice as many patients will require a chest drain as receive a pneumothorax)
Haemoptysis will also occur in about 5% of patients
This is useful if positive, but if negative is pretty useless (i.e. it could just means you missed the part of the lesion you wanted)
88
what are the other investigations for bronchial carcinoma
FBC – for detection of anaemia
LFT’s – to check for liver involvement
Biochemistry – hypercalcaemia, hyponatraemia
Increased Ca2+ – this will occur as a result of bone metastasis. May also be a result of secretion of parathyroid hormone.
Decreased sodium – this will occur as a result of adrenal involvement (Addisonianism).
89
what is mediastinoscopy
Just put a cut just above the sternal notch and stick a camera down – helps to see in the mediastinum because you can’t see this very well on x-ray – checks for nodes in cases of peripheral tumours
You can get to post tracheal lymph nodes best.
PET has reduced the need for this procedure – it used to be done in all patients – now its only done in cases where they can’t decide if there is spread or not
Presence of any mediastinal disease is a contraindication for surgery
The procedure itself requires general anaesthetic, and thus many patients aren’t fit for it.
90
what is the general prognosis rule for lung cancer
20% of the cases will survive to 12 months
6% will survive to 5 years
91
what is non-small cell carcinoma staged using
the TNM system
92
look up the TNM staging model
93
what are the two classifications of small cell carcinoma
limited or extensive
SCC is extremely aggressive and metastasis occurs early
94
what is limited small cell carcinoma
confined to one lung/hemithorax
may have spread to lymph nodes on the same side
95
what is extensive small cell carcinoma
distant metastasis, may have spread liver, bones, adrenals, brain, skin
96
what is the life expectancy for limited disease
on average, is around 3 months from presentation. with chemotherapy, this may be up to one year
97
what is the life expectancy for extensive disease
on average around 1 month at presentation. with chemotherapy it can improve to around 8 months.
the 5 year survival is 5%
98
what percentage of SCC and NSC respond to chemotherapy
90% of SCC but only 50% of NSC will
99
what is offered treatment wise for TNM State 1 NSC
operable – 70% survival at 5 years after surgery. This is quite low for such a small cancer (~2cm)
100
what is the treatment for TNM Stage 2 NSC
survival drops to 40% after surgery. This is because there are often tiny metastasis that you cannot see
101
what is the treatment for TNM Stage 2a NSC
25% survival – although many surgeons don’t like to operate on these. Adjuvant chemotherapy, given after the operation, improves survival by 5%
102
what is the treatment for TMN Stage 4 NSC
only chemotherapy offered. If you give no treatment – they have a 6% chance of being alive after 1 year. With chemotherapy, about 12% will still be alive after 1 year.i
103
in general, how long does chemotherapy expand life span for
extends lifespan by two months. however, only about a half of patients respond to chemotherapy
104
what percentage of cancers are suitable for surgery at presentation
only about 15-20%
105
what are the currently recommend chemotherapy regimens for small cell carcinoma
Cyclophosphamide + doxorubicin + vincristine + etoposide,
or
Cisplatin + radiotherapy if the disease is limited
106
what is the treatment regimen for chemotherapy
day one- bolus
day 14 - blood tests
107
what happens during the 3rd week of each cycle
you may have blood transfusions and other treatments that help you to recover before the next cycle
108
what classes who chemotherapy is available to
the WHO classification for performance status.
only available for those in 0-2 and under the age of 80
109
what is prognosis determined by if there are brain mets
survival drops to 1-2 months. prognosis is determined by the brain mets, and no longer by the primary tumour
110
why is surgery not appropriate for those over 6y5
as the operative mortality exceeds the survival rate
111
what is a contraindication for radiotherapy
poor lung function
112
what percentage of lung cancers are SCC and NSC
20% are small cell
80% are non small cell
113
what are the four types of non-small cell lung cancer
Adenocarcinoma (around 40% of total lung cancers)
Squamous cell carcinoma (around 20% of total lung cancers)
Large-cell carcinoma (around 10% of total lung cancers)
Other types (around 10% of total lung cancers)
114
what do small cell lung cancer cells contain
neurosecretory granules
115
what do these neurosecretory granules release and what does this mean SCC is responsible for
release neuroendocrine hormones. may be responsible for various paraneoplastic syndromes
116
what are the presenting features of lung cancer - 7
Shortness of breath
Cough
Haemoptysis (coughing up blood)
Finger clubbing
Recurrent pneumonia
Weight loss
Lymphadenopathy – often supraclavicular nodes are the first to be found on examination
117
the next questions are on the extra pulmonary manifestations of lung cancer
Lung cancer is associated with a lot of extrapulmonary manifestations and paraneoplastic syndromes. These are linked to different types and distributions of lung cancer. Exam questions commonly ask you to suggest the underlying cause of a paraneoplastic syndrome. Sometimes they can be the first evidence of lung cancer in an otherwise asymptomatic patient.
118
what do recurrent laryngeal nerve palsy patients present with
hoarse voice.
119
what is recurrent laryngeal nerve palsy caused by
a tumour pressing on or affecting the recurrent laryngeal nerve as it passes though the mediastinum
120
what is phrenic nerve palsy due to and what does it cause and present with
due to nerve compression, causes diaphragm weakness and presents with shortness of breath
121
what is superior vena cava obstruction caused by
a direct tumour compression on the superior vena cava.w
122
what does SVC obstruction present with
facial swelling, difficulty breathing, and dissented neck and upper chest veins
123
what is Pemberton's sign
where raising the hands over the head causes facial congestion and cyanosis
124
SVC obstruction is a medial emergency
125
what is Horner's syndrome a triad of
a triad of partial ptosis, anhideosis, and mitosis
126
what can Horner's syndrome be caused by
Pancoast tumour (found in the pulmonary apex) pressing on the sympathetic ganglion
127
what presents with hyponatremia that is related to lung cancer
syndrome of inappropriate ADH can be caused by ectopic ADH secretion by a small cell lung cancer
128
what can Cushing's be caused by
Cushing’s syndrome can be caused by ectopic ACTH secretion by a small-cell lung cancer.
129
what can hypercalcaemia be caused by
Hypercalcaemia can be caused by ectopic parathyroid hormone secreted by squamous cell carcinoma.
130
what is limbic encephalitis
paraneoplastic syndrome where small-cell lung cancer causes the immune system to make antibodies to tissues in the brain, specifically the limbic system, causing inflammation in these areas. This causes symptoms such as short-term memory impairment, hallucinations, confusion and seizures. It is associated with anti-Hu antibodies.
131
what is Lambert-Eaton myasthenic syndrome
Lambert-Eaton myasthenic syndrome is caused by antibodies against small-cell lung cancer cells. These antibodies also target and damage voltage-gated calcium channels sited on the presynaptic terminals in motor neurones. This leads to weakness, particularly in the proximal muscles. It can also affect the intraocular muscles, causing diplopia (double vision); levator muscles in the eyelid, causing ptosis; and pharyngeal muscles, causing slurred speech and dysphagia (difficulty swallowing). Patients may also experience dry mouth, blurred vision, impotence and dizziness due to autonomic dysfunction.
132
what are the NICE guidelines for suspected cancer
recommend offering a chest x-ray carried out within 2 weeks to patients over 40 with:
Clubbing
Lymphadenopathy (supraclavicular or persistent abnormal cervical nodes)
Recurrent or persistent chest infections
Raised platelet count (thrombocytosis)
Chest signs of lung cancer
133
what are the two KEY examination findings that automatically indicate an urgent chest x ray
finger clubbing and supraclavicular lymphadenopathy.
these are quick things to check for and can save a patients life
134
who else to NICE also recommend offering a CXR to
patients over 40 years old who have:
Two or more unexplained symptoms in patients that have never smoked
One or more unexplained symptoms in patients that have ever smoked or had asbestos exposure
135
what are the unexplained symptoms that NICE list
Cough
Shortness of breath
Chest pain
Fatigue
Weight loss
Loss of appetite
136
what is the first line investigation for lung cancer
chest x ray
137
what findings on a CXR suggest cancer
Hilar enlargement
Peripheral opacity (a visible lesion in the lung field)
Pleural effusion (usually unilateral in cancer)
Collapse
138
what is used in a CT staging scan
contrast enhanced scan using injected construct
139
what do PET-CT scans involve
PET-CT (positron emission tomography) scans involve injecting a radioactive tracer (usually attached to glucose molecules) and taking images using a combination of a CT scanner and a gamma-ray detector to visualise how metabolically active various tissues are. They help identify metastases by highlighting areas of increased metabolic activity.
140
what is EBUS
Bronchoscopy with endobronchial ultrasound (EBUS) involves endoscopy with ultrasound equipment on the end of the scope. This allows detailed assessment of the tumour and ultrasound-guided biopsy.
141
what is offered first line to patients with non-small cell lung cancer with disease isolated to a single area
surgery
142
what are the three options for removing a lung tumour
Segmentectomy or wedge resection involves removing a segment or wedge of lung (a portion of one lobe)
Lobectomy involves removing the entire lung lobe containing the tumour (the most common method)
Pneumonectomy involves removing an entire lung
143
what does a thoracotomy scar in your OSCEs indicate
either a lobectomy, a pneumonectomy, or lung volume reduction surgery for COPD.
144
what does a right-sided mini thoracotomy incision in a cardiology station likely mean
minimally invasive mitral valve surgery
145
what does absent breath sounds on an entire side indicate
a pneumonectomy
146
what do focal absent breath sounds suggest
a lobectomy
147
what were lobectomies and pneumonectomies used to treat in the olden days
TB
148
what is the most common subtype of lung cancer in non-smokers and females
adenocarcimona
149
why are patients kept in the department for 15 minutes after a contrast injectionn
in case of allergic reaction
150
what is the mechanism of action of Lambert-Eaton syndrome
autoantibodies that block acetyl-choline being released
the symptom is muscle weakness
151
what is the mechanism of action and symptoms of hypertrophic oestoarthropathy
new bone formation in periosteum in the forearms and lower legs
marked clubbing and pain
152
what is the diagnosis of cancer confirmed with
biopsy
153
how do most pet scans work
by injecting a radio tracer called fluorodeoxyglucose which is similar to naturally occurring glucose
154
what are the possible complications of a CT guided biopsy
pneumothorax
haemopytsis
155
what are the molecular markers that can be performed in a liver biopsy
EGFR
ROS1
ALK
BRAF
KRAS
156
why is it useful to identify mutations - what dos it allow for
allows for targeted drug therapy with tyrosine kinase inhibitors
157
what is another class of drugs used in advanced lung cancer
immune checkpoint inhibitors
158
what is the checkpoint protein on T cells
PD-1 is a checkpoint protein on T cells, ad binds to PDL-1 on cancer cells which results in the cancer cell evading attack
159
what drug are patients started on if they had a high PDL-1 status
pembrolizumab
160
when does immunotherapy related pneumonitis classically happen
within the first 3 months after starting therapy and presents with cough, shortness of breath
161
what is immunotherapy related pneumonitis treated with
It is treated with steroids, intravenous methylprednisolone in more severe disease, or oral prednisolone in milder disease.
162
