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Patient with haemoptysis, Shortness of breath

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Article in The Journal of the Association of Physicians of India · October 2014

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30 Journal of the association of physicians of india • vol 62 • october, 2014
cpc
Patient with Haemoptysis, Shortness of Breath and
Microscopic Haematuria
Yojana Gokhale*, Swati Bhide**, Ameet Dravid**
*
Professor of Medicine, In-
charge of Rheumatology, **Ex-
Resident in Medicine, Lokmanya
Tilak Medical College, Sion,
Mumbai
Introduction Proteins2+, 15-20RBCs/hpf, x-ray chest
revealed bilateral alveolar shadows with
W e present two patients who
presented to us with respiratory
symptoms (case 1 haemoptysis and
sparing of apices (Figure 3), ultrasound
kidneys was reported as small contracted
kidneys, sputum was negative for acid
shortness of breath, case 2 (cough and fast bacilli (5 samples) Patient was
shortness of breath) with microscopic clinically diag nosed as ‘Pulmonary
haematuria detected in routine urine renal syndrome’ and treatment with
examination. Both suffered from a similar Inj. Methyl Prednosolone 1gm daily for
disease. Timely intervention saved their 3 days followed by oral Prednisolone
lives and permanent organ damage in 1mg/kg was started and first pulse of
one. Cyclophosphmide 500mg was given,
awaiting serology. (Antineutrophilic
Case 1 Cytoplasmic Antibody- ANCA, Anti-
G B M a n t i b o d y , A N A) . H i s s e r u m
Forty three years old male from Dhule
tested positive for p-ANCA (by
district of Maharashtra presented to his
immnunoflurosecnce)and antibodies to
family doctor in December 2004 with
myloperoxidase (MPO by ELISA). His
malaise, anorexia, haemoptysis. After
serum tested negative for Anti- GBM and
baseline x-ray (Figure 1) and blood
anti nuclear anti body, cryoglobulins,
tests he was started on anti tuberculosis
HBsAg, and anti-HCV. So final diagnosis
treatment (ATT). Patient kept getting
was ANCA positive small vessel
recurrent haemoptysis for which repeated
vasculitis- microscopic poly angitis
x-ray chest were performed (Figure
presenting as PRS. He was dialysed
2). In January 2006 he got admitted
thrice ie till creatinine reduced to 3mg
to our hospital with haempotysis
/dl and kidney biopsy was performed.
and breathlessness. On
examination, pulse-96/min,
blood pressure- 180/100,
respiratory rate- 20/ min, he
wa s p a l e , h a d n o o e d e m a ,
raised jugular venous pressure
or cyanosis. There were
bilateral fine crepitations
on auscultation of chest, no
gallop or any organomegaly
was present. As per his old
records his serum creatinine in
August 2005 was 2mg/dl. His
investigations at our hospital
were as follows: Hemoglobin-
4.5gm/dl, WBC- 12000/cumm,
Erythrocute Sedimentation
Rate- 115mm at 1 hour, Urine Fig. 1 : Normal chest x-ray in a patient with haemoptysis
due to alveolar harmorrhage
Journal of the association of physicians of india • vol 62 • october, 2014 31
It revealed crescentic GN (>50% crescents). Oral
Cyclophospamide was given with dose adjusted for
creatinine clearance. He was discharged on creatinine
2mg/dl, Hb- 7.5gm. At 6 months creatinine 2.3 mg/dl,
Hb-10gm with out dialysis. At 9 months creatinine
3.8 mg/dl. Patient was then lost to follow up. Plasma
exchange, kidney biopsy specimen examination for
immunofluroscence and electron microscopy could
not be performed in him for lack of funds.
Case 2
F/45, had respiratory symptoms for 8 months,
initially upper respiratory (sneezing, nasal discharge
and stuffiness of nose) which were diagnosed as
allergic rhinitis by her doctor, later for her episodic
cough and shortness of breath she was investigated
and diagnosed as ‘probable Interstitial Lung Disease’
and treated with a short course of steroids on the basis
Fig. 2 : Bilateral alveolar shadows with apical sparing in
DAH
Fig. 3 : Chest x-ray in DAH A. before and B. after Inj Methyl Prednisolone
of lung function tests, chest x ray (which was normal)
and High resolution CT scan of chest (Figure 4).
After 8 months of treatment in private when she was
admitted with us in November 1997, she had severe
fatigue, with great difficulty doing her daily chores
like cooking. But other than a tired look on her face and
blood pressure 150/90, rest of the general and systemic
examination was normal. Respiratory physician who
was treating her, had told her husband that she had a
lot of functional element… BUT as per her records her
ESR was 135mm and urine examination revealed 120
RBCs /hpf!!! We suspected PRS and sent her blood for
ANCA, ANA, ANTI-GBM antibodies. She was c-ANCA
positive. Haemoglobin 8.5, WBC- 11,500/ cumm, Serum
creatinine 1mg/dl, Ca- 9mg/dl, P- 3.5mg/dl
We performed her kidney biopsy (Figure 5). The
report was ‘bit of kidney tissue showing multiple
glomeruli, most are sclerosed, only 14 relatively
preserved and show fibrinoid necrosis and crescents.
Biopsy consistent with the diagnosis of Wegener’s
Granulomatosis in end stage renal disease.’ As her
creatinine was 1mg/dl, we monitored her GFR. It
Fig. 4 : High resolution CT scan of chest in Case 2 showing
ground glass opacities and fibrotic strands
32 Journal of the association of physicians of india • vol 62 • october, 2014

Fig. 5 : Kidney biopsy (H & E) A. Most glomeruli sclerosed, fibrinoid necrosis (B) and crescent (C) in relatively preserved
glomeruli
Table 1 : Etiology of PRS or bilateral reticular shadows (case 2) with GGOs in
• Systemic Vasculitis (2/3rd ANCA +ve) right bases. Thus both have a systemic illness with GN
Wegener’s Granulomatosis and pulmonary involvement ie PRS.
Microscopic Polyangiitis Pulmonary Renal Syndrome (PRS), is a combination
Churg-Strauss syndrome of diffuse alveolar haemorrhage (DAH)and
Cryoglobulinemia glomerulonephritis (GN), in most cases RPGN. It
Henoch-Schonlein Purpura was first described by Good Pasture in 1919 1 . The
• Goodpasture’s Disease (< 5%) term Goodpasture syndrome was adopted in 1958 2
• Connective Tissue Disease and the pathogenic role of anti- glomerular basement
Polymyositis/Dermatomyositis membrane antibodies (anti-GBM) in some cases of
Progressive Systemic Sclerosis DAH and GN was proven 10 years later 3. An interesting
SLE, APLA study was conducted in Massachussate general
Primary Glomerular Disease hospital on 88 patients’ sera (sent for anti-GBM test
IgA nephropathy for DAH and GN from 1981-1993), after availability of
Post-Infectious GN ANCA test in the institute. It was found that 48 had
Membranoproliferative GN
ANCAs, six had anti-GBM and seven had both 4. It has
• Drug, Infections, Neoplasm
become clear now that several pathogenic mechanisms
underlie this clinical syndrome of DAH and GN and
Haematopoetic stem cell transplant
the term PRS is now used to describe the condition.
• Idiopathic Pulmonary Haemosiderosis
PRS is not a single disease, it has a differential
was 30ml/min. She was treated with Steroids (Oral diagnosis of its own (Table 1). Timely diagnosis of PRS
Prednisolone 1mg/kg for a month then tapered)and is important for associated high mortality (25-50%) 5 ,
Cyclophosphamide (100mg daily) for two years. Her need for Ventilatory support in 32- 50% and dialysis
GFR remained between 30-35 ml/min for next 5 years. dependence at 1 yr in up to 73% patients 6,7 if not timely
In 2003 ie after 5 years GFR was 50ml and now 15 adequately treated.
years later also it is maintained at 50ml/min while she
But there are problems with timely diagnosis in
is taking Prednisolone 2.5mg/day and Methotreaxate
ICU setting as common conditions like pneumonia,
10mg per week.
sepsis and cardiac failure are close differentials
Discussion and premorbid signs symptoms of PRS are often
nonspecific. Also as regards DAH 1. Patient may be
If we enumerate list of problems in our two patients asymptomatic for DAH, haemoptysis may be absent
: 1. Clinical Problems are Malaise, Anorexia, Weight in 1/3 rd patients. 2. On chest x-ray DAH may be
loss, fatigue, cough, shortness of breath, Recurrent misdiagnosed as infections like bronchopneumonia
Haemoptysis (in case 1) and 2. Laboratory Problems or tuberculosis or ARDS due sepsis, even raise
are Anemia, Leukocytosis, Elevated ESR, Active Urine creatinine may be attributed to MSOF, or it may also
Sediment, Renal Failure, X-ray chest-DAH (in case 1), be misdiagnosed as pulmonary oedema due to renal
HRCT Chest: Bilateral Ground glass opacities (case 1) failure. Chest x-ray is normal in 20% patients with
Journal of the association of physicians of india • vol 62 • october, 2014 33
Table 2 : Investigations in PRS
For Etiloogy For Confirming Diagnosis
• ANCA by IF (if positive anti-PR3/ • BAL
MPO)
• ANTI-GBM ANTIBODY • BIOPSY (Lung, kidney)
• ANA
• CRYOGLOBULINES
• C3, C4
• ACLA, LA
• HBsAg, Anti-HCV
Sputum, blood cultures to R/O
infection
Serial x-ray chest
DAH. 8 On HRCT chest DAH produces ground glass
opacity, a pattern seen in many conditions and it
generally gets reported as ILD and then one may not
consider DAH as a diagnostic possibility.
Diagnostic criteria used for DAH are not uniform
in all reports. Hemoptysis, alveolar opacities, anemia,
hypoxemia, and/or elevated carbon monoxide transfer
factor (TLCO) have been used to define DAH in previous
series. BAL is more sensitive than any other criteria for
the diagnosis of DAH. Fiberoptic bronchoscopy will
show haemorrhages from many bronchopulmonary
segments. Regarding Bronchoalveolar lavage – BAL is
more sensitive than any other criteria for the diagnosis
of DAH. It may show grossly pink/ red BAL in acute
cases or haemosiderine leden macrophages (>30%).
Bronchoscopy provides a means of demonstrating
AH and collecting specimens for culture. If facilities
are available one should proceed with it. It is done in
studies reported by chest physicians.
(DLCO)Carbon monoxide diffusion capacity is used
as an adjunctive test to diagnose DAH, it increases in
DAH due to presence of haemoglobin in alveoli. DLCO
is helpful if the test is performed in the 1 st 48 hours of
DAH. An increase in DLCO of 30% over baseline or a
value of ≥ 130% predicted is reported to be suggestive
of DAH and is observed in 25% patients of DAH. 9
Obtaining DLCO measurement is not practical at night
and in critically ill patient.
A firm diagnosis of PRS is obtained by clinical
presentation, serologic results and histological results
although obtaining material for the latter may present
practical difficulty in a critically ill patient.
Tissue diagnosis should be obtained when cause
of DAH is not confirmed by clinical/ serological
and bronchoscopic evaluation. Open lung biopsy is
preferred over trans bronchoscopic lung biopsy. Lung
biopsy shows RBCs/ hemosiderine laden macrophages
in alveolar spaces. Evidence of capilaritis in the form of
alveolar wall distruction and neutrophillic infiltration
is rare.
Diagnosis of GN is not a problem in presence of
active urinary sediment and rising creatinine. Gold
standard for diagfnosis of PRS are lung/ kidney biopsy.
Regarding Kidney biopsy --On light microscopy,
kidney biopsy in important causes of PRS shows
focal necrotising and creascentic GN. But direct IF
aids in the diagnosis of Anti GBM if there are linear
IgG deposits, Lupus if granular IgG deposits and no
or minimal deposits in pauciimmune GN- WG/MPA.
But in patients with high serum creatinine immediate
kidney biopsy may not be possible. And one has to
start treatment on strong clinical suspicion, awaiting
laboratory reports.
The classic clinical presentation of DAH consists of
hemoptysis and dyspnea in the setting of ‘unexplained
drop in haemoglobin’ and a chest radiograph showing
bilateral air-space consolidation with apical sparing.
However, each of these features are nonspecific and
variable eg history of haemoptysis is absent in 1/3 rd
cases. Onset is generally abrupt but shadows may
resolve with out treatment (as in case 1) and recur.
On chest x ray - Complete radiographic resolution
takes 3-4 day but may occur in 1 day, after Inj. Methyl
Prednisolone, thus making ‘serial chest x-rays’
important in diagnosis awaiting laboratory reports.
At the resolution stage, a reticular pattern is usually
observed for two weeks. After multiple episodes of
alveolar hemorrhage, it is possible to find a residual
interstitial pattern as a consequence of developing
pulmonary fibrosis (HRCT of Case 2).
All investigators have reported a prodrome and
an acute presentation. The prodrome consists of non-
specific constitutional symptoms like malaise, fatigue,
Fever, weight loss, Arthralgias, myalgias, Episcleritis,
purpuric rash that preceede acute presentation by
an average of 3-6 months. 10 Up to 8-12 months of
prodrome has been reported. 7 And acute presentation
is with cough, haemoptysis, hypoxic respiratory
failure and RPGN. If patient is diagnosed in prodrome
(as in case 2) we can salvage kidneys (note number of
sclerosed glomeruli in Figure 5 with in 8 months of
onset of symptoms). Those cases of PRS not related
to Goodpasture’s, syndrome usually have clinical
features suggesting such diagnosis as vasculitis, acute
synovitis, multiplex mononeuritis or previous history
of SLE. In PRS related to infections like leptospirosis,
presence of other features of disease like jaundice
aid in diagnosis and treatment is directed towards
primary disease.
Table 2 gives list of investigations in PRS. Presence
of autoantibodies is a predominant feature of PRS,
it aids in diagnosis and in determining course of
illness in PRS. Outcome is better in patients with
PRS associated with ANCA than those with ant-GBM
antibodies. 11
Treatment of PRS consists of Steroids and
Cyclophosphamide for all, plasma exchange for severe
cases (serum creatinine > 5.7mg/dl, life threatening
34 Journal of the association of physicians of india • vol 62 • october, 2014
DAH), supportive care (ventilator/ dialysis) when
necessary and novel therapies (Rituximab, IVIG, ATG,
Factor VII, ECMO) for refractory cases. There is a
place for antibiotics in PRS in SLE patients as infection
is often a precipitating cause. 12 Plasma exchange in
patients presenting with serum creatinine >5.7mg/
dl has shown to improve renal survival at one year 13
43% Vs 19%.
Conclusion
Recognition of PRS is established by clinical
features, serology and histology and may present
practical difficulties in a critical care setting. The
occurrence of prodromal illness of significant duration
in most cases indicates a need for earlier diagnosis
with the use of serological tests.
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