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Pulmonary Hemorrhage in Henoch-Schnlein Purpura:Case Report and Systematic Review of the English Literature

Srinivas Rajagopala, MD, DM,* Vineeta Shobha, MD, DM,

Uma Devaraj, DNB,

George DSouza, MD, DNB,

and Isha Garg, MD

Background:Diffuse alveolar hemorrhage (DAH) is a rare complication of Henoch-Schnleinpurpura (HSP) and data on its prevalence, management, and outcomes are scant.

Objectives:To enable evidence-based management of DAH in HSP.

Methods:A case report and a systematic review were conducted of all reported cases of DAHcomplicating HSP in the English literature.

Results:DAH predominantly affects older male children and adults with HSP. The occurrence ofDAH in HSP is rare and the reported prevalence ranged from 0.8% to 5%. DAH occurred variably

after the diagnosis of HSP, ranging from 2 days to 18 years. Hemoptysis (75%), drop in hemo-globin (74%), and chest infiltrates (94%) were the most common clinical findings. Lung biopsyshowed leukocytoclastic vasculitis with alveolar hemorrhage (69.2%) or only alveolar hemorrhage(31.8%) with variable IgA staining by immunofluorescence. DAH was frequently severe and 50%of the patients required mechanical ventilation. Cyclophosphamide and pulse methylprednisolonefor DAH was associated with better outcomes, particularly in patients who were already receivingsteroids at the time of DAH. Steroids and immunosuppressants were administered for a medianduration of 9 and 4.5 months, respectively. Systemic recurrences (27.7%) and recurrences of DAH(8.3%) were frequent. DAH was associated with high mortality (27.6%) and morbidity (persistenturinary abnormalities, 12%; chronic renal failure, 9%; complications of therapy, 27%).

Conclusions:DAH is a life-threatening complication in HSP. Current protocols use pulse meth-ylprednisolone and cyclophosphamide for 6 months.

2013 Elsevier Inc. All rights reserved. Semin Arthritis Rheum 42:391-400Keywords:diffuse alveolar hemorrhage, Henoch-Schnlein purpura, hemoptysis, respiratory failure

Henoch-Schnlein purpura (HSP) is a small-ves-sel vasculitis presenting with a tetrad of cutane-ous purpura, arthritis, abdominal pain, and

nephritis. HSP usually affects children and is an acute,self-limited illness that lasts about 4 weeks with recur-rences in 25%. Diffuse alveolar hemorrhage (DAH) is anunusual complication of HSP and data on its frequency,management, and outcomes are scant. We describe a clas-

sic case of DAH occurring in HSP and review all reportedcases of DAH complicating HSP in the English literature.

CASE REPORT

A 55-year-old man presented with a rash over his legs andback, abdominal pain, joint pain, and hematochezia of 15

days duration. He was a farmer by occupation, did notsmoke or drink alcohol, and did not have any significantpast medical history. On examination he was afebrile,normotensive, with respiratory rate of 16 breaths/minand a pulse rate of 100 beats/min. He had extensive non-palpable purpura over the legs and back, pedal edema, and

joint tenderness in the knee, ankle, and interphalangealjoints of both upper limbs. The rest of the physical exam-ination was unremarkable. Investigations showed a he-moglobin count of 11.3 g/dl (normal 12 to 14) and aplatelet count of 2.34 105/l (normal 1.5 to 4.5 105)

*Department of Pulmonology, St Johns Medical College Hospital, Sarjapur Road,

Bangalore, India.

Department of Medicine, St Johns Medical College Hospital, Sarjapur Road,

Bangalore, India.

Department of Pathology, St Johns Medical College Hospital, Sarjapur Road,

Bangalore, India.

The authors have no conflicts of interest to disclose.

Address reprint requests to Srinivas Rajagopala, MD, DM, Consultant, Department

of Pulmonary Medicine, Liver Intensive Care, Global Hospitals and Health City,

Perumbakkam, Chennai, India 600100. E-mail: [email protected].

VASCULITIS

3910049-0172/13/$-see front matter 2013 Elsevier Inc. All rights reserved.http://dx.doi.org/10.1016/j.semarthrit.2012.07.004
mailto:[email protected]:[email protected]://dx.doi.org/10.1016/j.semarthrit.2012.07.004http://dx.doi.org/10.1016/j.semarthrit.2012.07.004mailto:[email protected]

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with normal leukocyte counts. Urine examination re-vealed 10 to 12 leukocytes/hpf (normal 2 to 3/hpf), 6 to 8erythrocytes/hpf with albuminuria; no casts were ob-served. Serum creatinine was 0.9 mg/dl (normal 0.6 to1.0). Ultrasound of the abdomen showed wall thickening

of the jejunum and minimal ascites. Stool occult bloodwas positive. Human immunodeficiency virus enzyme-linked immunosorbent assay, antinuclear antibody,antineutrophil cytoplasmic antibody by immunofluores-cence, andn antiglomerular basement antibody enzyme-linked immunosorbent assay tests were all negative.Twenty-four-hour urine protein was 3.94 g/24 h/m2

(normal 30 g). Liver function tests, electrocardio-gram, and chest radiographs were normal. Skin biopsyshowed evidence of leukocytoclastic vasculitis; immuno-fluorescence showed pericapillary IgA and C3 deposition(Fig. 2). Renal biopsy showed evidence of focal prolifera-

tive glomerulonephritis and IgA/C3 deposition (Fig. 3).Colonoscopy was normal. A diagnosis of HSP with focalsegmental glomerulonephritis and gastrointestinal bleed

was made. He was started on 1 mg/kg prednisolone, andpantoprazole on day 4 of admission; his joint pains andgastrointestinal bleed subsided. On day 7 of admission, hedeveloped sudden breathlessness, hemoptysis, and cough.Chest radiographs showed bilateral consolidation (Fig. 1,left) with a drop in hemoglobin (7.6 g/dl). Arterial blood

gas analysis showed PaO2/FiO2 of 325 (normal 450 to

500), PaCO2 of 30 mm Hg (normal 40 4), HCO3 of22mm Hg (normal 24 4), and pH 7.48 (normal, 7.40 0.04). Repeat electrocardiogram was normal and echocar-diography confirmed normal ejection fraction with novalvular defects or evidence of infective endocarditis.Bronchoscopy was normal; bronchoalveolar lavage fluidshowed numerous hemosiderin-laden macrophages. A di-agnosis of DAH was made, and oxygen at 2 l/min, 1 g/dpulse methylprednisolone for 3 days, and pulse cyclo-phosphamide 750 mg/m2 were administered; 1 mg/kgprednisolone was continued after 3 days. He becameasymptomatic with normalization of findings on Chest

Radiography (Fig. 1,right) and was discharged on day 21of admission. However, his course was complicated byrecurrent gastrointestinal bleed, worsening edema, and aurinary tract infection. He was initiated on diuretics, enal-april and levofloxacin. Cyclophosphamide was subse-quently changed to azathioprine because of persistentneutropenia. He remains asymptomatic at 6 months offollow-up on 10 mg prednisolone and azathioprine buthas persistent albuminuria.

MATERIALS AND METHODS

Literature Search and Study Selection

Two of the authors (RS and VS) conducted a systematicsearch of the literature independently in MEDLINE,OVID, and CINAHL databases using the terms He-noch-Schnlein purpura AND alveolar hemorrhage,lung, and pulmonary hemorrhage. A second search

was then performed using the terms anaphylactoid pur-pura AND alveolar hemorrhage, lung, and pulmo-nary hemorrhage. In addition, another search was per-formed using the term Henoch-Schnlein purpura andabstracts were searched for possible cases of alveolar hem-orrhage secondary to HSP. Only those articles that werereported in English literature and included patients with

Figure 1 Composite figure shows bilateral alveolar infiltrateswith air bronchograms (left) at the time of diagnosis ofalveolar hemorrhage. Chest radiograph (right) after treat-ment with pulse methylprednisolone and cyclophosphamideshows normalization of radiologic findings.

Figure 2 Photomicrograph of low-power view of the skinbiopsy (10, left) shows neutrophilic infiltration into thedermis and fibrinoid vasculitis. Immunofluorescence micros-copy (right, arrow) of the skin biopsy shows deposition of IgAand C3 and absence of IgG and IgM in the same areas. (Colorversion of figure is available online.)

Figure 3 Photomicrograph of high-power view of the kidneybiopsy (40, PAS stain) showing evidence of focal prolifera-tive glomerulonephritis. Immunofluorescence shows deposi-tion of IgA and C3 and absence of IgG and IgM. (Colorversion of figure is available online.)

392 Diffuse alveolar hemorrhage in Henoch-Schnlein purpura

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diagnosed HSP fulfilling the 1990 criteria of the Ameri-can College of Rheumatology (1)or the HSPEULAR/PRINTO/PRES Ankara 2008 classification (2) and (1)alveolar hemorrhage documented by at least 2 of the fol-lowing (a) drop in hemoglobin, (b) hemoptysis, (c) newpulmonary infiltrates, (d) hemosiderin-laden macro-phages on bronchoalveolar lavage fluid, or (2)surgical orautopsy specimens showing alveolar hemorrhage with or

without leukocytoclastic vasculitis were included for anal-ysis. The study was approved by the institutions ethicsboard.

Data Extraction

Both abstracts and full text articles, where available, werereviewed. Data were extracted in a predesigned data ex-traction form regarding the age, sex, clinical features,mode of diagnosis of diffuse alveolar hemorrhage, time todiagnosis of DAH after diagnosis of HSP, comorbidities,kidney, skin, and lung biopsy findings, treatment beforeDAH and after the onset of alveolar hemorrhage, theduration of immunosuppressant administered, and out-comes. Data were extracted and expressed in a descriptivefashion (mean, SD).

RESULTS

Our search yielded 3662 references. This included 36cases of diffuse alveolar hemorrhage in Henoch-Schnleinpurpura (Table 1)in 28 published reports.Full text orabstracts were available for all 36 cases (3-30) in the arti-cles reviewed. An additional 20 reports were excludedbecause they reported cases in other languages (31-38)

or did not include patients with alveolar hemorrhage(39-50).The median age of DAH in HSP was 16.5 years (4

months to 78 years). Fifty percent (n 32)(3,6,9,10,12,14,21,22,24,25,27-30)were older than 20years at presentation. Male patients were affected morefrequently (M:F, 20:12). The occurrence of alveolar hem-orrhage in HSP is rareandthereported prevalence rangedfrom 0.8% to 5% (4,11,19,22). Several large series ofpatients with HSP, both in children (51,52) and in adults(53,54), have not reported any case of DAH.

Alveolar hemorrhage occurs in the setting of extensivesystemic vasculitis due to HSP. The organs involved werekidney (94.4%), skin (86.1%), gastrointestinal tract(75%), and joints (72.7%). Patients without cutaneousinvolvement atpresentation had documentedrash eitherpreviously (14)or later in the disease course (18). One-fourth of the patients had other organ involvement, com-monly neurologic (5,6,11,17,30) (13.8%), upper respira-tory tract (3,8,17,18) (11.1%), or cardiac (11,23) (5.5%).Overlap with microscopic polyangiitis, as demonstratedby fibrinoid necrosis in subcutaneous vessels, medium-sized arteries, and positive antineutrophil cytoplasmic an-tibody, was reported in 2 patients (12,30) (5.5%). Mostpatients did not have other comorbid illnesses (88.9%).

The diagnosis of HSP was based on the characteristicclinical syndrome in most patients. Leukocytoclastic vas-culitis was demonstrated in most patients in whom a skinbiopsy was performed (6,9,11-14,17,18,21-25,27-30)(n 21), even when normal areas were biopsied (14).However, IgA positivity wasseen in 57% (n 21) only(6,12-14,17,22,23,25,28-30), especially when biopsy wasattempted later in the disease course. Renal vasculitis wasvery common (94.4%, n 31/33); hematuria and/orproteinuria (33%,n 12/33) and renal failure in 47%(n 17/33) (7,9,11-13,15-17,19,20,22,23,27,29,30)

were the most common manifestations. The mean serumcreatinine was 3.2 0.57 mg/dl at presentation and5.6% were on hemodialysis (n 2/33) (14,25). Ne-phrotic syndrome was seen in 8.3% (n 3/36)(14,20,27). Biopsy commonly demonstrated mesangio-proliferative glomerulonephritis (44.4%, n 8/18)(8,9,12,15,18,24,26,29) buta wide variety of other le-sions were observed (Table 2). Immunofluorescence wasobtained in 44.4% (n 16/36) and demonstratedIgA

and C3 in 93.7% (n 15/16) of these patients (6,8-10,12,13,15,17-19,21,26,27,29,30). Concurrent gastro-intestinal vasculitis was seen in 75% (n 27/36); abdom-inal pain (42.7%, n 15/36) and malena (25%, n 9/36) were most common but gastroenteropathy (5.6%,n 2/36) and intestinal obstruction (2.8%, n 1/36)

were also seen.Alveolar hemorrhage occurred variably after other or-

gan involvement, ranging from 2 days to 18 years after thediagnosis of HSP. Hemoptysis (75%), drop-in hemoglo-bin (74%), and chest infiltrates (94%) were present inmost patients, suggesting the late recognition of alveolar

hemorrhage. Bronchoalveolar lavage for hemosiderin-laden macrophages was attempted in 16.7% only. Thechest radiograph commonly demonstrated alveolar infil-trates or ground-glass opacities (80.6%); however, reticu-lonodular infiltrates mimicking interstitial lung disease

were seen in 13.9% (11,14). Pleural effusions were alsoobserved in 16.7% and were often massive, requiring tubethoracostomy (4,9,12,16,18,30).

Lung biopsy was available in 36.1% (n 13/36) andshowed leukocytoclastic vasculitis with alveolar hemor-rhage (69.2%,n 10/13) (3,5,6,10,12,13,15,23,25,27)or only alveolar hemorrhage without capillaritis (31.8%,n 3/13) (7,17,30). IgA was positive in only 50% (n 3/6) (6,10,12)of these lesions. Electron microscopic ex-amination was reported in 2 cases (12,13) and one ofthem demonstrated electron-dense deposits in the capil-lary basementmembrane and the interstitium of the alve-olar walls (12).

Overall, 27.8% of HSP patients who experiencedDAH died (n 10/36) (3,5,6,10-12,17,23,25,30). Un-treated alveolar hemorrhage was rapidly fatal (10,17).Most of the patients (61%) were on treatment with ste-roids for systemic vasculitis at the time of onset of alveolarhemorrhage (47%). DAH was frequently severe and 50%(n 18/36) of the patients required mechanical ventila-

S. Rajagopala et al. 393

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Table 1 Summary of All Reported Cases of Henoch-Schnlein Purpura with Diffuse Alveolar Hemorrhage in English Literature

Refe rences No.Age/

Sex

Clinical Features

KidneyBiopsy IF

Diagnosis of DAH

Time toLungSkin Arthritis Kidney GI Others

Dropin

Hb Hemoptysis Radiology BALF Others

Jacome etal.

1 45/F Proteinuria;hematuria

Melena Epistaxis Not done NA Alveolar NA Lung Bx LCV neg; DAHIgA NA

NA

Cream etal.

5% (4/77) NA Proteinuria Pain NA Not done NA ConsolidationPE (75%)

NA Pleurisy Severalweeks

Weiss et al. 1 8/M Proteinuria Pain Neurological Not done NA Alveolar NA Lung BxLCV;IgA NA

NA

Kathuria etal.

1 57/M Proteinuria;ESRD

P ain Neurological CGN IgA; n oC3

NA Con solidation NA LCV, DAH IgA; noC3 lung,skin Bx

5 yr

Leathermanet al.

1 10/F Proteinuria;Cr 5.2

Pain No FSGN; IgA;C3 neg

NA Alveolar NA Lung Bxdone;DAH, LCVneg;IgA

8 w k

Payton etal.

1 17/M Proteinuria;hematuria,RF

No Nasalstuffiness

MPGN IgA,IgM C3

NA No NA No Bx done NA

Shichiri etal.

1 53/F Proteinuria;hematuria,RF Cr 1.4

Bleed Diabetes,urinarytractinfection

MPGN IgA,IgM C3

ConsolidationPE (R)

NA Skin Bx: LCV IgA NA

2 wk

Markus etal.

1 78/M No Melena;ulcer

1 previousepisodeof DAH

CGN; IgA Con solidation NA DAH , LCV,IgA-Intra-alveolarIgA

3 wk

References No. (If Series)Age/

Sex

Clinical Features

Kidneybiopsy IF

Diagnosis of DAH

Time toLung

Involvement PSkinArthritis/

ArthralgiaNephritisCr

(mg/dl) GI Others

Dropin


Olson etal.

4/169 (2.3%) 14/F Hematuria,Cr NA

Pain None Not done A lve ol ar Y es No l ung b io ps y; s ki nbiopsy IgA-leukocytoclasticvasculitis (75%);IgA-FSGN (1),IgA-CGN (1); IgA DPGN (1), NA

(1)

15 wk N

4.5/F Hematuria;RF Cr 2.1

Pain None Reticulonodular No 28 wk N

15/M Hematuria;RF Cr 1.9

Pain/blood

No Alveolar;interstitial

No 3.5 wk N

16/M RF Cr 3.8;hematuria

P ain Neurological/cardiac

Alveolar;interstitial

No 7 wk P

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Table 1 Continued


Sex

Clinical Features

Kidneybiopsy IF

Diagnosis of DAH

Time toLung

Involvement PSkinArthritis/

ArthralgiaNephritisCr

(mg/dl) GI Others

Dropin


Yokose etal.

1 77/M Hematuria;RF; Cr6.5

No Fibrinoidnecrosis?MPN

MPGNIgAC3

Alveolar; largePE

NA Skin Bx LCV IgA,autopsy lungLCV, DAH IgA

2 d N

Wright etal.

1 14/F Hematuria;RF; Cr

2.2

Melena Lung biopsyLCV, DAH

IgM,C3,IgA

DPGN;IgA,

IgM,C3

Alveolar NA Skin Bx LCV; IgA 3 wk P

Mallat etal.

1 29/M Nephroticsyndrome;ESRD ondialysis

No DiagnosedHSP 11 yr;recurrentbouts 4

No Reticulonodular Yes IgA C3 skin BxLCV of normalskin

11 yr N

Reznik etal.

1 14/F RF; CR NA Pain No MPGN;IgA,C3

Alveolar NA L ung biopsy LCV,DAH; IgA NA

1 wk R

Carter etal.

1 15/M Nephritis;Cr 1.3

Pain/blood

None;intercostaltubedrainage

No Alveolar;massivetransudativePE

NA No skin, renal, orlung biopsy done

1 wk N


Sex

Clinical Features

Kidney BiopsyIF

Diagnosis of DAH

Time toLung

InvolvementT

PrSkin Arthritis Nephritis GI Others

Dropin


Paller etal.

2 12/M Hematuria;RF; Cr1.7

No Epistaxis;stroke,seizures

CGN; IgA _ A lve ola r N A S ki n B x L CV IgA

1.5 wk Pre

0.4/F Hematuria;Cr NA

No None NA A lve ol ar N A S ki n B x L CV I gANA; autopsylung BxDAH; noLCV

64 wk No

Vats et al. 1 7/M Not atonset;day4

Hematuria;Cr 0.5

Colickypain;bleed

Sinusinvolvement;surgery

MPGNIgA,C3

Alveolar;pleuraleffusions

NA Skin Bx: IgA-LCV; sinus,jejunumLCV-

1 wk No

Besbas et

al.

1/550 (0.18%) 6/M Hematuria;

RF Cr 2.8

No None DPGN; IgA,

C3

Alveolar NA None 1 wk Pu

Al-Harbi etal.

1 9/F Nephroticsyndrome;RF Cr 5.4

Pain;bleed

None No biopsy Alveolar NA None 1.5 wk Pre

Teixeira etal.

1 45/M Nephritis; Cr1.0

Pain Occult alveolarhemorrhage;previouspulmonarytuberculosis

FPGN IgA, C3mesangium

No rma l Y es S ki n B x no rma l;no lung Bx

3 m o O c

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tion (3,5,6,10-13,15-20,25,28,29) for a mean durationof 26 4.8 days (n 10). Continuation of oral steroids,often at higher doses, was associatedwith a mortality rateof 27. 2% (n 3/11) (3,5,6,11). Pulse methylpred-nisolone, at a varying number of boluses, was adminis-tered after the occurrence of DAH in 11 patients (mor-tality 27.2%,n 3/11). Pulse methylprednisolone along

with cyclophosphamide (11,17,19,20,23), pulse cyclo-phosphamide followed by azathioprine (7,8,29), or my-cophenolate mofetil (27)and cyclosporine A (26)wereadministered in 11 patients and had the least mortality

rate observed (9%, n 1/11). Untreated DAHhad auniformly fatal outcome (n 3/3, 100%) (6,17,30). Ste-roids and immunosuppression were administered for amedian duration of 9 months (range, 10 days to 36months) and 4.5 months (2.5 to 36 months), respectively.

The total duration of reported follow-up (mean, SE)was 1.6 (0.5) months (n 19). Recurrence of vasculitiswas seen in 27.7%, including 4 patients (11.1%) withrecurrent DAH (7,16,22,25). Morbidity due to DAH

was also common and persistent urinary abnormalities(8,9,11,18)(12%), chronic renal failure (9%) (14,25),

Table 2 Summary Findings of All Reported Cases of Henoch-Schnlein Purpura with Diffuse Alveolar Hemorrhage in theEnglish Literature

Parameter Value

Age (median, range) 16.5 (4 mo to 78 yr), N 32Kidney biopsy (50%, N 18/36) MPGN (44.4%, N 8/18), FSGN (16.7%, N 3/18), DPGN (5.5%,

N 1/18), CGN (27.8%, N 5/18)Hyalinized glomeruli (5.5%, N 1/18)

Kidney biopsy immunofluorescence(44.4%, N 16/36)

IgA, C3 positive (93.75%, N 15/16), IgA, C3 negative (6.3%,N 1/16)

Time to lung involvement from onsetof illness (mean, range)

3 wk (2 d to 18 yr) (N 29)

Diagnosis of diffuse alveolarhemorrhage

Drop in hemoglobin (74%, N 27), hemoptysis (75%, N 36), chestradiology finding (94.4%, N 36), bronchoalveolar lavage (16.7%,N 36)

Chest radiology findings Consolidation/ground glass opacity (80.6%, N 36)Reticulonodular opacity (13.9%, N 36)Normal (5.6%, N 36)Pleural effusions (16.7%, N 36)

Leukocytoclastic vasculitis (LCV) onlung biopsy

69.2% (N 9/13); DAH alone 31.8% (N 4/13)

Immunoglobulin A positive on lungbiopsy

Surgical or autopsy (N 6/13); 50% (N 3/6)

Treatment before DAH None 38.9% (N 14/36)Oral steroids 50% (N 18/36)Pulse methylprednisolone 11% (N 4/36)

Treatment after onset of DAH None 8.3% (N 3/36)Oral steroids alone 30.5% (N 11/36)Methylprednisolone pulse alone 30.5% (N 11/36)Steroids and immunosuppression 30.5% (N 11/36)

Mechanical ventilation 50% (N 36)Duration of mechanical ventilation

(mean, SE)26 4.8 d (N 10)

Duration of steroid therapy median,range

9 mo (10 d to 36 mo, N 11)

Duration of immunosuppression(median, range)

4.5 mo (2.5-36 mo, N 6)

Recurrences of vasculitis 27.7%(N 10)

None 72.2% (N 36), all systemic 19.4% (N 7/36), PH alone11.1% (N 4/36)

Complications ofimmunosuppression 27% (N 11)

Zoster 9% (N 11), neutropenia 9% (N 11), anaphylaxis 9%(N 11)

Mortality 27.8% (N 10/36)Morbidity Persistent hematuria, albuminuria 12% (N 33), chronic renal failure

9% (N 33)

M, Male; F, Female; NA, not available; , present; absent; Cr, creatinine; DAH, diffuse alveolar hemorrhage; GN, glomerulonephritis;MPGN, Mesangioproliferative glomerulonephritis; FSGN, Focal segmental glomerulonephritis; CGN, Cresentric glomerulonephritis; DPGN,diffuse proliferative glomerulonephritis; PE, pleural effusions; R, right-sided; Bx, biopsy; LCV, leukocytoclastic vasculitis; IgA, ImmunoglobulinA; C3, complement 3; CYC, cyclophosphamide; AZA, azathioprine; MP, methylprednisolone; MV, mechanical ventilation; ESRD, end stagerenal disease; MPN, microscopic polyangiitis; PH, pulmonary hemorrhage.


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and complications of therapy (27%) (11,13,17,19)werefrequently observed.

DISCUSSION

HSP is an acute, self-limited small-vessel vasculitis char-acterized by depositionof immunoglobulin A (IgA) im-mune complexes (55,56). It is predominantly a disease ofchildren, with the highest prevalence between 4 and 7years (70 per 100,000) (55).

Age at onset and nephritis at presentation in HSP areimportant determinants of severity (57,58). The older ageof this cohort and high prevalence of nephritis suggestDAH occurs in patients at risk of recurrence of systemicvasculitis.

DAH is exceedingly rare in HSP and large series haveoften not reported any cases of DAH (52,53). Data fromthe retrospective studies of Cream et al. (4) and Nadrouset al. (22) have suggested a prevalence of 1.6% to 5% forovert alveolar hemorrhage. Differences in reported prev-

alence are probably due to case selection bias.The high frequency of clinically evident alveolar hem-

orrhage and the use of bronchoscopy in only 16.7% ofpatients with DAH related to HSP suggest late clinicalrecognition. In alveolar hemorrhage, clinically evident he-moptysis is present in only 33% of patients at presenta-tion because the total alveolar volume is large and canaccommodate bleeding without apparent symptoms;early bronchoscopy is recommended for diagnosis (59).Recurrent unrecognized DAH may be associated withreticular infiltrates mimicking an interstitial lung diseaseand was observed in 13.9% of patients (11,22). Subclin-

ical reductions of transfer factor of the lung for carbonmonoxide (TLCO) with active vasculitis (60), theassoci-ation of reduced TLCO with systemic relapses (60,61),and the finding of hemosiderin-laden macrophages in theabsence of pulmonary symptoms and normal radiographs(21)suggest that incipient alveolar hemorrhage may bemore common than is clinically evident. The prognosticimplication of subclinical alveolar hemorrhage, however,remains unclear.

Corticosteroids arenot recommended in patients withuncomplicated HSP (62,63); however, in patients withnephritis, pulse methylprednisolone followed by oral cor-ticosteroids plus azathioprine or cyclophosphamide is ef-fective in reversing clinical nephritis and preventing dis-ease progression (55,64). Patients with DAH secondaryto HSP capillaritis are treated with a similar regimen (59).Given the severity of DAH, it is unlikely that significantdelays existed after the diagnosis of DAH was made.However, delays of 2 to 3 weeks after onset of DAH(9,28)to the administration of steroids were seen, sug-gesting that the recognition of DAH was delayed. Mostpatients were on oral steroids for systemic vasculitis beforethe onset of DAH, indicating that steroids alone are inef-fective. At least 11% of patients had already received 3doses of pulse methylprednisolone just before the onset of

DAH for systemic vasculitis. Also, patients had a recur-rence of DAH with pulse methylprednisolone alone (25)and responded to cyclophosphamide pulse after failingpulse methylprednisolone for DAH (20). In patients onsteroids at the time of DAH, pulse methylprednisolonefollowed by cyclophosphamide for a median duration of 6months was the most commonly reported treatment reg-imen and was associated with a mortality rate of 9% (n 1/11). A high frequency of vasculitis recurrence (27.7%)and morbidity (27%) was seen.

DAH is a rare complication of HSP and often occurs inadults. Clinical recognition is delayed, with high morbid-ity and mortality. DAH is frequently severe, requiringmechanical ventilation. Pulse methylprednisolone andcyclophosphamide are associated with the least mortality,particularly in patients on steroids at the time of DAH.Further multicentric observational studies are required todefine the optimal regimen and duration of treatment inDAH related to HSP.

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