A LIFE-THREATENING COMPLICATION IN CONNECTIVE TISSUE

Acta Medica Mediterranea, 2014, 30: 1267
A LIFE-THREATENING COMPLICATION IN CONNECTIVE TISSUE DISEASES: TWO CASE
REPORTS
MARGIOTTA DOMENICO PAOLO EMANUELE, ZARDI ENRICO MARIA, ALEMANNO PAMELA, MARIGLIANO BENEDETTA, PIPITA
MARIA ELENA, AFELTRA ANTONELLA
Integrated Research Center, Clinical Medicine and Rheumatology Dep., Campus Bio-Medico University of Rome, Italy
ABSTRACT
Here we discuss diagnosis and management of DAH in two patients affected by systemic lupus erythematosus and granulomatosis with Polyangiitis. Multiple infections complicated the clinical course of DAH in both patients. A combination of therapies including antibiotics, anti-viral and antifungal treatment caused a good response and greatly contributed to the safe and full recovery of
DAH in both cases.
Key words: Diffuse Alveolar Haemorrhage, Granulomatosis Poliangiitis, Systemic Lupus Erythematosus.
Received May 18, 2014; Accepted September 02, 2014
Introduction
Diffuse alveolar haemorrhage (DAH), caused
by the disruption of the alveolar-capillary basement
membrane with severe bleeding into the alveolar
spaces is an uncommon life-threatening complication that may affect patients with connective tissue
diseases(1).
In this report, we discuss the background of
the abrupt onset of DAH in two patients affected by
two different connective tissue diseases [systemic
lupus erythematosus (SLE) and granulomatosis
with Polyangiitis (Wegener’s)], in which, diagnostic
clinical course, treatment and management were
very critical.
Case 1
A 23-year-old girl was transferred to our
department from another Hospital, for fever resistant to antibiotics, anemia, dyspnea and suspected
flare of Systemic Lupus Erythematosus (SLE). She
was diagnosed with SLE at just 15 years of age and
treated with NSAIDs, high doses steroids and
hydroxychloroquine. On admission to our
Department, she was apyretic, eupnoic (sO2 99%)
and tachycardic (HR 110 bpm) with diffuse joint
pain. The pulmonary examination showed absence
of breath sounds at both bases whereas, abdomen
and heart were normal; the chest radiography
showed lifting hemi-diaphragms. Blood examination confirmed the presence of anemia (haemoglobin 6.8 g/dL). Blood cultures, pharyngeal secretions, urine, sputum, vaginal fluid, serology for bacterial or viral infections (hepatitis viruses, HIV, adenovirus, VDRL, parvovirus B19, citomegalovirus,
salmonella, brucella, toxoplasma) were all negative.
Echocardiography, abdominal and transvaginal
sonography were normal. Blood transfusion, antibiotic and antifungal therapy was administered
(teicoplanin 400 mg/day and fluconazole 400
mg/day), whereas methylprednisolone dosage was
reduced to a 1 mg/kg/die. 48 hours after admission,
she developed hyperpyrexia (≥ 40°C), associated
1268
with desaturation (sO2 77%), tachypnea, abdominal
breathing, tachycardia (HR 150 bpm) with atrial
fibrillation and altered state of consciousness. The
haemogasanalysis showed signs of acute respiratory
failure with a high lactate value(2). After treatment
with high flux oxygen, the patient underwent an
emergency chest CT that showed diffuse areas of
“ground glass” parenchymal consolidation, with air
bronchogram in both lower lobes, bilateral hilar
enlargement, mild pleural and pericardial effusion
and axillary lymphadenopathy (figure 1). The bronchoalveolar lavage, showing a rising quote of red
blood cells, was compatible with DAH.
Figure 1: Chest CT showing bilateral diffuse areas of
“ground glass” parenchymal consolidation.
Microbiological cultures on BAL showed herpes simplex virus type 1 and aspergillus fumigatus.
Then, the patient was shifted to the intensive care
unit to be intubated and mechanically ventilated;
temporary tracheostomy was also performed. The
patient received blood transfusions due to anemia
(7 g/dL) and was treated with acyclovir (250 mg i.v.
3 times a day and then orally 200 mg 4 times a day)
for 15 days, voriconazole (4 mg/kg i.v. 2 times a
day and then orally 300mg/day) for two months and
high doses of steroid (methylprednisolone 1g/day
i.v. for three days then reduced to 1 mg/kg/day i.v.).
Intravenous immunoglobulin (0.4 g/Kg/die for 5
days) was also started.
After one week, she had a significant improvement of clinical conditions and she was extubated.
Inflammatory indices were reduced and chest radiography was normal. She was shifted back to our
department where antifungal therapy (voriconazol)
was continued at the same dosage (300 mg/day,
orally) whereas the steroid (methylprednisolone)
was progressively reduced. She was discharged
after 1 month with oral prednisone 25 mg (later
reduced at 15 mg) and hydroxychloroquine 200
mg/day. After six months of follow up, the patient
is in good clinical conditions and she is now taking
Margiotta Domenico Paolo Emanuele, Zardi Enrico Maria et Al
oral prednisone 7.5 mg/day and hydroxychloroquine 200 mg/day. She did not present flare of SLE
anymore.
Case 2
The medical history of a 74-year-old man
started in 2010 with headache, fever and migrants
arthralgias, lasting several months and responsive
to therapy with NSAIDs and acetaminophen.
In 2013, due to the new onset of fever, fatigue,
bilateral episcleritis, migrants arthralgias, he was
admitted to our Department. After admission, a
severe worsening of renal function (creatinine of
4.6 mg/dL) proteinuria (1426 mg/24h) and the presence of urinary erythrocyte cylinders was observed,
together with dyspnea, elevation of inflammatory
markers (ESR 120 mm/h, C reactive protein 150
mg/dL) and positive low titer of ANA (1:80) and cANCA (1:20). Renal biopsy was performed which
showed diffuse proliferative extracapillary
glomerulitis framework, compatible with granulomatosis with Polyangiitis (Wegener’s). The patient
received therapy with steroid bolus for three days
(methylprednisolone 1g daily and then 1 mg/kg/day
i.v.), but during the treatment presented hemoptysis,
progressive worsening of dyspnea and acute respiratory failure. A CT chest showed multiple confluent areas of increased parenchymal density and diffuse pulmonary ground-glass in the parenchyma of
both lungs, consistent with DAH (figure 2).
Figure 2: Chest CT showing diffuse areas of bilateral
“ground glass” parenchymal consolidation.
The bronchoalveolar lavage showed the presence of a rising quote of red blood cells and a high
titer positivity for CMV. Due to very critical condition renal insufficiency (creatinine of 4.8 mg/dL)
hypoxia (desaturation 75% in course of Non
Invasive Ventilation), anemia (haemoglobin 5.4
g/dL), the patient was shifted to the Intensive Care
Unit, where he was subjected to blood transfusions
A life-threatening complication in connective tissue diseases. Two case reports
and to prolonged invasive mechanical ventilation
for 20 days. Antiviral therapy with acyclovir (500
mg i.v. 3 times a day and then orally 400 mg 4
times a day) was started for a month. After extubation, because of persistence of a worsened renal
function and oliguric state, the patient was hydrated
and underwent 5 cycles of hemodyalisis (CVVHD).
After haemodynamic stabilization, and improvement of renal function, nine cycles of therapeutic
plasmapheresis were also performed to reduce the
amount of immunocomplexes and, soon, the clinical condition ameliorated. The patient was discharged in good general conditions with oral steroid
therapy (prednisone 30 mg/day) and cyclophosphamide (100 mg/day). His total duration of hospital stay was two months. One month after discharge
the patient presented acute polyneuropathy with left
palpebral ptosis and legs paresis.
1269
BAL. Interestingly, Aspergillus Fumigatus was also
found in case 1. High rates of viral and fungal
infections are reported during DAH [5]. The coexistence of opportunistic infections during DAH is
often associated with(9) and complicates the clinical
course leading to a delayed diagnosis. Moreover,
opportunistic infections are like to worsen the prognosis, making it difficult to establish adequate therapeutic strategies.
Intravenous immunoglobulins, antiviral and
antifungal treatment may favour a good clinical
response.
Plasma exchange treatment and hemodyalisis
may be also useful where indicated(10, 11).
To date, plasma exchange is recommended as
an adjunctive treatment for patients with severe
renal and/or alveolar haemorrhage, although, definitive evidence supporting the use of plasmapheresis
in DAH associated with AAV is lacking.
Discussion
Conclusion
Here we expose diagnostic, therapeutic strategy and management of the DAH on two patients
with different connective tissue diseases.
In the case 1 a young woman with a flare of
SLE developed DAH. DAH complicating SLE is a
severe, rare event that affects only from 1 to 5.4%
of these patients(3), predominantly young women
with a median age of 29 years(4), with a mortality
ranging from from 23% to 92%(3) and an overall
survival amounted in only 53%, despite the
increased usage of cyclophosphamide and plasmapheresis(5). A high prevalence of infection is associated to DAH in SLE patients(6).
However, a 100% survival is also reported in
patients receiving antibiotics at the onset of symptoms(7).
In the case 2 an old man with a rapidly evolving granulomatosis with polyangiitis (Wegener’s),
after developing acute kidney injury, a sudden DAH
arose. Likewise case 1, also case 2 required
mechanical ventilation. DAH associated with
ANCA associated vasculitis (AAV) increases the
relative risk of death by 8.6 times making these
autoantibodies one of the strongest predictors of
early mortality(8).
Several topics of particular interest are present
in these cases.
Both cases DAH developed as sudden complication of flare of autoimmune disease.
In both cases, viral infection by herpesviridae
(HSV1 in case 1 and CMV in case 2) was present in
Several complications, from mild to severe,
may affect patients with connective tissue diseases(12-17).
The DAH is one of more severe of these, since
it may be a fatal event that we may better counter
provided that the diagnosis is rapidly made and an
aggressive combined treatment is instituted.
Despite the major therapeutic advances in
DAH, morbidity and mortality remain high and disease relapses occur frequently, although the reported mortality varies among the different studies due
to the heterogeneity of the disease, patients and different treatments. In accordance with others(7) we
believe that the precocious use of anti-infective
therapy, concomitant with immunomodulants in
case 1 and plasma exchange in case 2 have given a
real contribute to the resolution of the disease; the
great benefit that both patients had from mechanical
ventilation is also to be emphasized. Also we
believe that high prolonged doses of steroid may be
ineffective and favour development of infections(18)
although immunosuppressant therapy with metilprednisolone bolus for three days, in spite of suspected infection, may be useful to control the
autoimmune disease reducing the organ damage.
Further control trials with a major uniformity
in protocols of treatment are advisable to understand what are the best therapeutic strategies in the
management of this life-threatening complication in
connective tissue diseases.
1270
Margiotta Domenico Paolo Emanuele, Zardi Enrico Maria et Al
References
1)
2)
3)
4)
5)
6)
7)
8)
9)
10)
11)
12)
13)
14)
15)
16)
Collard HR, Schwarz MI. Diffuse alveolar hemorrhage. Clin Chest Med 2004; 25: 583-92.
Newsome BR, Morales JE. Diffuse alveolar hemorrhage. South Med J 2011; 104: 269-74.
Badsha H, Teh CL, Kong KO, Lian TY, Chng HH.
Pulmonary hemorrhage in systemic lupus erythematosus. Semin Arthritis Rheum 2004; 33: 414-21.
Patel JJ, Lipchik RJ. Systemic Lupus-Induced Diffuse
Alveolar Hemorrhage Treated With Extracorporeal
Membrane Oxygenation: A Case Report and Review of
the Literature. J Intensive Care Med 2014; 29: 104-9.
Todd DJ, Costenbader KH. Dyspnoea in a young
woman with active systemic lupus erythematosus.
Lupus 2009; 18: 777-84.
Rojas-Serrano J, Pedroza J, Regalado J, Robledo J,
Reyes E, Sifuentes-Osornio J, Flores-Suárez LF. High
prevalence of infections in patients with systemic lupus
erythematosus and pulmonary haemorrhage. Lupus
2008; 17: 295-9.
Santos-Ocampo AS, Mandell BF, Fessler BJ. Alveolar
hemorrhage in systemic lupus erythematosus: presentation and management. Chest 2000; 118: 1083-90.
Lin Y, Zheng W, Tian X, Zhang X, Zhang F, Dong Y.
Antineutrophil cytoplasmic antibody-associated vasculitis complicated with diffuse alveolar hemorrhage: a
study of 12 cases. J Clin Rheumatol 2009; 15: 341-4.
Cardenas-Garcia J, Farmakiotis D, Baldovino BP, Kim
P. Wegener’s granulomatosis in a middle-aged woman
presenting with dyspnea, rash, hemoptysis and recurrent eye complaints: a case report. J Med Case Rep
2012; 6: 335.
Wilfong EM, Seo P. Vasculitis in the intensive care
unit. Best Pract Res Clin Rheumatol 2013; 27: 95-106.
Haupt ME, Pires-Ervoes J, Brannen ML, KleinGitelman MS, Prestridge AL, Nevin MA. Successful
use of plasmapheresis for granulomatosis with
polyangiitis presenting as diffuse alveolar hemorrhage.
Pediatr Pulmonol 2013; 48: 614-6.
Zardi EM, Afeltra A. How to predict subclinical atherosclerosis in systemic lupus erythematosus. Does noninvasive imaging hold the key? Rheumatology 2011;
50: 821-823.
Zardi EM, Vernieri F, Navarini L, Taccone A,
Sambataro G, Alemanno P, Margiotta D, Afeltra A.
Systemic lupus erythematosus patients with and without
neuropsychiatric manifestations: a neck and transcranial duplex Doppler study. Int J Immunopathol
Pharmacol 2012; 25: 1157-65.
Zardi EM, Zardi DM, Lazarevic Z, Santucci S,
D’Errico F, Afeltra A, Tonioni S. Transient global
amnesia as the first symptom of primary antiphospholipid syndrome: a case report. Int J Immunopathol
Pharmacol 2012; 25: 275-80.
Ferri GM, Gigante A, Ferri F, Amoroso D, Zardi E,
Papa A, De Galasso L, Amoroso A. Urine chemokines:
biomarkers of human lupus nephritis? Eur Rev Med
Pharmacol Sci 2007; 11: 171-179.
Trimarchi M, Sinico RA, Teggi R, Bussi M, Specks U,
Meroni PL. Otorhinolaryngological manifestations of
granulomatosis with polyangiitis (Wegener ’s).
Autoimmun Rev 2013; 12: 501-505.
17)
18)
Belhassen-Garcia M, Velasco-Tirado V, Alvela-Suarez
L, Carpio-Perez A, Lledias JP, Novoa N, IglesiasGomez A, Cordero-Sanchez M. Spontaneous pneumothorax in Wegener’s granulomatosis. Case report
and literature review. Semin Arthritis Rheum 2011; 41:
455-60.
Gonzalez-Echavarri C, Pernas B, Ugarte A, RuizIrastorza G. Severe multiorganic flare of systemic lupus
erythematosus successfully treated with rituximab and
cyclophosphamide avoiding high doses of prednisone.
Lupus 2014; 23: 323-6.
Abbreviatons: anti-double strained DNA antibodies
(anti-dsDNA), anti-nuclear antibodies (ANA), Systemic Lupus
Erythematosus (SLE), computed tomography (CT), continuous
veno-venous hemodialysis (CVVHD), C-Reactive protein
(CRP), erythrosedimentation rate (ESR), Haematocrit (Hct),
Haemoglobin (Hb), heart rate (HR), Mean Corpuscular
Volume (MCV), Non steroidal anti-inflammatory drugs
(NSAIDs), oxyhemoglobin saturation (sO2), platelets (PLTs),
red blood cells (RBC), white blood cells (WBC), liter (L) milliliter (mL), microliter (µl), kilogram (Kg), gram (g), milligrams
(mg), nanograms (ng), millimeter (mm), hour (h), oxygen saturation (sO2), hearth rate (HR), intra-vein (i.v.)
_________
Correspoding author
ZARDI ENRICO MARIA
Integrated Research Center, Clinical Medicine and
Rheumatology Dep., Campus Bio-Medico University of Rome,
via Alvaro del Portillo 21, 00128, Rome
(Italy)

Download Report