Lepr Rev (2010) 81, 129– 136
CASE REPORT
A case of erythema nodosum leprosum reaction
with diffuse alveolar haemorrhage, successfully
treated by pulsed methylprednisolone
NARONGWIT NAKWAN*, SUNISA THAICHINDA**
& NARONGSAK NAKWAN***
*Department of Medicine, Hat Yai Medical Education Center,
Hat Yai Hospital, Songkhla, Thailand
**Division of dermatology, Department of Medicine, Hat Yai
Medical Education Center, Hat Yai Hospital, Songkhla, Thailand
***Department of Pediatrics, Hat Yai Medical Education Center,
Hat Yai Hospital, Songkhla, Thailand
Accepted for publication 27 June 2010
Summary We present a case of erythema nodosum leprosum (ENL) reaction with
diffuse alveolar haemorrhage (DAH) in a patient who completely recovered with
pulsed methylprednisolone. Our case illustrates that ENL could be a predisposing
factor for DAH and a high dose of corticosteroid plays an important role in
successfully treating such a patient.
Introduction
Diffuse alveolar haemorrhage (DAH) is a life-threatening condition. Although a variety of
etiologies could predispose to the development of DAH, erythema nodosum leprosum (ENL)
has in the past never been described as a cause. ENL is a Type 2 reactional leprosy and
commonly occurs in borderline leprosy and lepromatous leprosy.1 Because ENL is an
immune-complex mediated disease, the clinical features could, therefore, be present in the
involvement of multiple organ systems and include such diseases as polyarthritis, myositis,
neuritis, iridocyclitis and lymphadenitis.2 – 3 In this report we present a case of ENL with
DAH which was successfully treated by pulsed methyprednisolone.
Correspondence to: Narongwit Nakwan, M.D, Department of Medicine, Hat Yai Medical Education Center, Hat
Yai Hospital, Songkhla, Thailand 90110 (Tel: þ66 8 1898 4566; Fax: þ 66 7 4411 333; e-mail: [email protected])
0305-7518/10/064053+08 $1.00
q Lepra
129
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N. Nakwan et al.
Case Report
An 18 year old man was admitted with complaints of multiple enlarged painful subcutaneous
nodules for the past month, a low grade fever, a loss of 6 kg of body weight during the
preceding 3 months and arthralgia. The patient had no known exposure to tuberculosis and
was not taking any drugs prior to visiting our hospital. On examination the patient had a low
grade fever, multiple cervical lymphadenopathy, mild hepatosplenomegaly and polyarthritis
Figure 1. Multiple erythematous dermal and subcutaneous nodules distributed over (A) face, (B) upper trunk.
Erythema nodosum leprosum with diffuse alveolar haemorrhage
131
Table 1. Monitoring of haematologic and clinical chemistry laboratory values during admission
Period of treatment
Admission
date
Haemoglobin (g/dL)
13·3
Hematocrit (%)
40
Total WBC count
12 000
( £ 109/L)
Neutrophils (%)
70
Lymphocytes (%)
25
Monocytes (%)
3
Eosinophils (%)
2
Platelet counts ( £ 109/L)
196,000
Prothrombin time
14
(10·5 –13·5 sec)
International normalize
1·14
ratio (1–1·3)
Partial thromboplastin time
30
(22·8– 31 sec)
SGPT (10–30 IU/L)
10
SGOT (9–43 IU/L)
12
Alkaline phosphatase
110
(35–110 IU/L)
Total serum bilirubin (mg/dL)
0·7
Blood urea nitrogen (mg/dL)
10
Creatinine (mg/dL)
0·8
Erythrocyte sedimentation
140
rate (mm/hr)
24 hours later
72 hours later
Presented with
acute dyspnea
Started pulse
and haemoptysis methyprednisolone
8·8
25·9
19 300
68
22
6
4
288,000
13
1·12
28
28
40
112
0·6
14
1·0
5 days later
Finished
pulse
2 weeks
methyprednisolone later
8·8
25·9
19 300
13
38
12 500
12
37
11 000
90
6
2
2
288,000
13·5
75
23
3
2
275,000
70
25
2
3
188,000
1·13
27·5
25
38
102
0·8
12
0·9
in his knees, elbows, wrists and fingers. He had multiple discrete symmetrical, ill-defined,
painful erythematous dermal and subcutaneous nodules on top of crusted ulcers and
infiltrative erythematous plaque over his face, upper trunk and limbs (Figure 1).
There was no thickening of the peripheral nerves, sensory loss or muscular weakness.
A skin biopsy was performed from the right forearm lesions. Serial haematology and clinical
chemistry were performed (Table 1).
The urine analysis was negative. The abdominal ultrasonography revealed mild
hepatosplenomegaly and the chest radiography showed normal findings.
At 24 hours after admission, the patient suddenly developed massive haemoptysis with
severe hypoxia, along with a new-onset anemia (hemoglobin level, 8·8 g/dL) compared to the
hospital admission value of 13·3 g/dL (Table 1). A physical examination of the chest revealed
bilateral late, fine, inspiratory crackles in the lower lung fields. The chest radiography
revealed bilaterally diffuse alveolar opacities (Figure 2A).
The patient needed intubation and mechanical ventilation. The provisional diagnosis was
suggestive of alveolar pulmonary haemorrhage.
Approximately 72 hours later, the patient continued to have worsening haemoptysis and a
repeat chest radiography showed progressive bilateral alveolar infiltrations. There was no
growth of pathogenic bacteria or evidence of fungal infection in the blood and bronchial fluid.
The Ziehl-Neelsen acid-fast stains on the sputum also were negative. The test results for the
immunological tests are shown in Table 2.
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N. Nakwan et al.
A skin biopsy revealed diffuse nodular infiltration of numerous foamy histiocytes,
lympho-histiocytes and giant cells with clumps of fragment bacilli (globi) within the few
foamy cells, including predominant polymorphic neutrophil infiltration throughout the
dermis (Figures 3A and 3B).
Scanty granular bacilli were found by Wade-Fite staining and these findings were
compatible with erythema nodosum leprosum (Figure 4).
Figure 2. (A) Chest radiographs while clinical symptoms suspected DAH. (B) 3 days after administration of pulsed
methylprednisolone.
Erythema nodosum leprosum with diffuse alveolar haemorrhage
133
Table 2. Results of immunologic tests on admission
Test
Result
Anti-HIV antibody
Anti-HCV antibody
HBs Ag
Anti-streptolysin-O
Antinuclear antibody
Anti-dsDNA antibody
Rheumatiod factor
Antineutrophil cytoplasmic autoantibody
Leptospira antibody
Serum C3 (75– 135 mg/dL)
Serum C4 (10– 40 mg/mL)
C-reactive protein (4–6 mg/L)
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
Negative
98
24
24·6
The slit skin smear was not performed. The patient was conclusively diagnosed with ENL
with diffuse alveolar haemorrhage.
Thereafter, he was administered 1 gm of intravenous methylprednisolone daily for 3 days.
The patient’s pulmonary symptoms improved dramatically after the second dose of pulse
corticosteroids. The repeated chest radiography after 3 days of pulse therapy showed the
resolution of opacities (Figure 2B).
As a result, the corticosteroid was switched to oral prednisolone (1 mg/kg/day) combined
with multibacillary multi-drug therapy (MB-MDT) which consisted of a monthly dose of
600 mg rifampicin and 300 mg clofazimine and a daily dose of 100 mg dapsone and 50 mg
clofazimine for 1 year. The prednisolone was tapered off, 5– 10 mg every 4 weeks over
6 months. There was no growth of Mycobacterium tuberculosis in his blood or sputum after
3 months of incubation. The patient completed a follow-up check, which showed a clearance
of all symptoms and that he was clinically well. The follow-up slit skin smears from routine
sites showed negative findings.
Discussion
This report describes a highly unusual event of diffuse alveolar haemorrhage (DAH)
developing in association with erythema nodosum leprosum (ENL). Many causes of DAH
have been described to have pulmonary capillaritis that include systemic vasculitis, collagen
vascular diseases, antiphospholipid syndrome, Gooodpasture’s syndrome and Behc¸et’s
syndrome,4 whereas ENL has not been previously described as a cause. Because DAH has a
variety of pathogenic mechanisms, establishing the diagnosis should be confirmed by the
histopathology of samples obtained by bronchoscope or of bronchoalveolar larvage.4
Unfortunately, we did not have a bronchoscope available, thus the diagnosis of DAH in our
patient is purely clinical and not proven. In our case, we needed to exclude a possible cause of
DAH, particularly systemic vasculitis such as SLE, small vessel vasculitis, antiphospholipid
syndrome, and other autoimmune disease including infectious diseases. However, our case
was absence of the characteristic clinical features of such diseases as well as the negative
specific autoantibodies including antinuclear antibody, antineutrophilic cytoplasmic
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N. Nakwan et al.
Figure 3. (A) Histological appearance of the whole dermis (Haematoxylin and eosin; original magnification £ 10).
(B) The infiltration was composed of numerous foamy histiocytes with globi and numerous neutrophils infiltration
(Haematoxylin and eosin; original magnification £ 100).
antibody, anti-dsDNA, rheumatoid factor and anti-cardiolipin, which are of benefit in making
the diagnosis.4 We were unable to investigate any antibodies, including anti-glomerular
basement membrane, because of the limitations in our ability.
The skin lesions, skin smear and pathological features are useful for the diagnosis of
leprosy, classifying the type and deciding on the appropriate treatment. Unfortunately, we
did not perform a slit skin smear on our patient because of the life-threatening situation.
Erythema nodosum leprosum with diffuse alveolar haemorrhage
135
Figure 4. Modified Ziehl-Neelsen acid fast stain was revealed scanty granular pink hue of mycobacterial debris.
(Original magnification £ 40).
Therefore, ENL was consequently diagnosed on the basis of the clinical features and the
pathological findings of the skin biopsy. Even though the evidence of a skin smear and the
clinical of leprosy have been limited, our patient was presenting features of multibacillary
leprosy according to the Ridley-Jopling classification. Moreover, our patient also has to be
clinically considered in the differential diagnosis of other diseases that present with
symptoms of tender nodules, such as erythema nodosum, other panniculitides, Sweet
syndrome, and nodular vasculitis. However, histological findings are helpful for a definite
diagnosis.
It is not known whether the association between ENL and DAH is coincidental or whether
there is some common pathogenic link. Several studies have postulated that ENL is an immunecomplex mediated process resulting in the overproduction of immunoglobulin, complement
and cytokines, whereas DAH is described by pulmonary capillaritis as a result of the deposition
of immune-complexes leading to an inflammatory cascade, finally followed by alveolar
hemorrhage.2 – 9 Based on these observations, we speculate that the immune-complex mediated
process in ENL may have played an important role in the development of DAH. Thus, we
suggest that the demonstration of immune-complex deposition in lung specimens by
immunofluorescent microscopy would be beneficial for a definitive diagnosis of this entity.
Diffuse alveolar haemorrhage is a life-threatening condition with a high mortality; a
patient needs prompt diagnosis and aggressive management steps in treatment. Whereas, the
occurrence of DAH with ENL has not been previously proposed, the data on treating this
condition is limited. Because we speculated that the immune-complex mediated process may
have played an important role in the development of DAH in ENL, corticosteroid should be a
useful treatment. Our patient was therefore administered pulse methylprednisolone and he
responded well to this regimen. However, corticosteroid is also the mainstay of management
in ENL and pulmonary capillaralitis causing DAH.4,5
In conclusion, this case report highlights the rare occurrence of diffuse alveolar
hemorrhage in ENL. Such a case illustrates that the immune-complex process may play an
important role in the pathogenesis of DAH and that intravenous administration of a high dose
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N. Nakwan et al.
corticorsteriod may be beneficial for an ENL patient with DAH. The diagnosis of DAH is
unclear and needs to be confirmed by histopathology to the find the possible cause.
Acknowledgements
The authors wish to thank Associated Professor Sauvarat Auepemkiate, Department of
Pathology, Faculty of Medicine, Prince of Songkha University and Dr. Walaiorn
Pratchyapruit, Institute of dermatology, Ministry of Public Health, for their kindness in
performing the histological examination of the skin biopsy specimen mentioned in this paper.
References
1
2
3
4
5
6
7
8
9
Kumar B, Dogra S, Kaur I. Epidemiological characteristics of leprosy reactions: 15 years experience from north
India. Int J Lepr Other Mycobact Dis, 2004; 72: 125 –133.
Wemambu SNC, Turk JL, Waters MFR, Rees RJW. Erythema nodosum leprosum: a clinical manifestation of the
arthus phenomenon. Lancet, 1969; 2: 933 –935.
Cuevas J, Rodriguez-Peralto JL, Carrillo R, Contreras F. Erythema nodosum leprosum: reactional leprosy. Semin
Cutan Med Surg, 2007; 26: 126–130.
Green RJ, Ruoss SJ, Kraft SA et al. Pulmonary capillaritis and alveolar hemorrhage update on diagnosis and
management. Chest, 1996; 110: 1305–1316.
Marlowe SNS, Lockwood DNJ. Update on leprosy. Hosp Med, 2001; 62: 471–476.
Sheagren JN, Block JB, Trautman JR, Wolff SM. Immunologic reactivity in patients with leprosy. Ann Intern Med,
1969; 70: 295 –302.
Rao TD, Rao PR. Serum immune complexes in erythema nodosum leprosum reactions of leprosy. Indian J Lepr,
1988; 60: 189 –195.
Moran CJ, Ryder G, Turk JL, Waters MF. Evidence for circulating immune complexes in lepromatous leprosy.
Lancet, 1972; 16: 572– 573.
Lahiri R, Sandoval FG, Krahenbuhl JL, Shannon EJ. Activation of complement by mycobacterium leprae requires
disruption of the bacilli. Lepr Rev, 2008; 79: 311 –314.