Henoch-Schönlein Purpura in children: not only kidney but also lung

Background Henoch-Schönlein Purpura (HSP) is the most common vasculitis of childhood and affects the small blood vessels. Pulmonary involvement is a rare complication of HSP and diffuse alveolar hemorrhage (DAH) is the most frequent clinical presentation. Little is known about the real incidence of lung involvement during HSP in the pediatric age and about its diagnosis, management and outcome. Methods In order to discuss the main clinical findings and the diagnosis and management of lung involvement in children with HSP, we performed a review of the literature of the last 40 years. Results We identified 23 pediatric cases of HSP with lung involvement. DAH was the most frequent clinical presentation of the disease. Although it can be identified by chest x-ray (CXR), bronchoalveolar lavage (BAL) is the gold standard for diagnosis. Pulse methylprednisolone is the first-line of therapy in children with DAH. An immunosuppressive regimen consisting of cyclophosphamide or azathioprine plus corticosteroids is required when respiratory failure occurs. Four of the twenty-three patients died, while 18 children had a resolution of the pulmonary involvement. Conclusions DAH is a life-threatening complication of HSP. Prompt diagnosis and adequate treatment are essential in order to achieve the best outcome.


Background
Henoch-Schönlein purpura (HSP), also known as anaphylactoid purpura or, most recently, IgA Vasculitis (IgAV), is the most common leukocytoclastic systemic small-vessel vasculitis in childhood [1]. It is usually characterised by non-thrombocytopenic purpura, with typical purple, non-blanching papules, localised primarily on the lower extremities and buttocks. It can also be associated with abdominal discomfort, joint symptoms such as arthritis or arthralgia of large joints of the lower extremities, and risk of renal involvement [2].
The range of clinical manifestations of HSP is very broad, varying from asymptomatic microscopic hematuria to proteinuria and acute kidney injury (AKI) of various degrees up to rapidly progressive glomerulonephritis with significant risk of chronic renal impairment [3]. Other possible organ involvement includes cerebral vasculitis, ureteral or bladder disease, and scrotal, penile or testicular hemorrhage [4][5][6].
Piram et al., in a review published in 2013, estimated the annual incidence of HSP in children to be between 3 and 26.7/100,000, demonstrating that it occurs two to 33 times more frequently in infants than in adults [7].
HSP is usually a self-limiting disease with an average duration of 4 weeks; it can have a remitting-relapses course especially within 3 months after initial resolution and rarely, when complicated, it can be fatal [8].
Although the etiology remains unknown, a possible link between genetic predisposition and environmental factors are considered crucial for the pathogenesis of HSP [9,10].
The diagnosis of HSP is based on clinical findings. The diagnostic criteria for HSP were recently revised by various study groups (EULAR European League Against Rheumatism, PRINTO Pediatric Rheumatology International Trials Organisation and PRES Pediatric Rheumatology European Society), and are listed in Table 1 [11,12].
Pulmonary involvement in HSP is a rare but severe complication and its presence increases the vasculitis morbidity and mortality rates [13][14][15][16].
Lung involvement in children with HSP is extremely rare. In particular, sub-clinical lung impairment without respiratory symptoms assessed by pulmonary function tests has been seen during the active phase of the disease, suggesting that the course of the disease involves a malfunction of the alveolar-capillary membrane due to the deposition of immune complexes containing IgA within the vessels of the alveolar septa [17][18][19].
Chaussen et al. reported a decrease in lung transfer for carbon monoxide (TLCO) in 28 out of 29 patients with HSP without pulmonary symptoms, with normal lung volumes and normal blood gas values, although mild radiological signs of interstitial lung involvement were observed in 18 of 26 patients. In all cases, the TLCO values normalised after complete clinical recovery [20].
TLCO impairment is associated with granular immune complex deposition, neutrophilic interstitial infiltration (acute inflammation), fibrin deposition and consequent fibrinoid necrosis, finally resulting in a thickening of the capillary wall. Nuclear debris may be present in the interstitium, representing leukocytoclasis [21,22]. This hypothesis is supported by the results of autopsies on patients who died of diffuse alveolar hemorrhage (DAH), which were characterised by pulmonary edema with intra-alveolar hemorrhage, interstitial fibrosis, arterial neutrophilic infiltrate, loss of nuclear staining in the alveolar walls and septa, and capillary wall necrosis. The immunochemistry examination shows granular deposition of IgA along the alveolar septa, suggesting an immune pathogenesis [23,24].
The absence of IgA on the lung biopsy does not rule out a potential role in the pathogenetic mechanism, due to the rapidity of the immunofluorescence changes, for example on the skin, where IgA disappears just a few days after its deposition [25,26].
Massive lung involvement such as DAH is rare, especially in the pediatric age. Patients with pulmonary hemorrhage have kidney involvement in up to 95% of cases, more than double the percentage of patients with no pulmonary involvement, sign of the presence of a more severe disease [27,28].
The aim of this review is to provide a critical appraisal of the medical literature regarding the lung involvement in HSP in children.

Methods
A research of the literature was performed in PUBMED database, using the terms "Henoch-Schönlein Purpura", "anaphylactoid purpura", "Diffuse alveolar hemorrhage", "Pulmonary Involvement", "Children". Only those articles that were reported in English literature and included pediatric patients (0-18 years) with a HSP and lung involvement were included for this narrative review. We found 23 cases between 1979 and 2019, and we described symptoms, diagnostic findings, treatment and outcomes.

Results
Between 1979 and 2019, there were 23 pediatric casereports of children with HSP who developed DAH. The main findings of these case-reports are described in Table 2.
The average age at the onset of HSP with pulmonary involvement was 10.2 years, with little difference between males (12 cases) and females (11 cases).
Almost all children with pulmonary hemorrhage had renal involvement, ranging from hematuria often associated with proteinuria, to nephritis or nephrotic proteinuria through to AKI [8, 10, 14, 15, 25-27, 29-37, 39]. The co-occurrence of rapidly progressive glomerulonephritis and DAH is also known as "pulmonary renal syndrome" and it is primarily related to an autoimmune etiology. However, Gd-IgA1 pathway is probably involved, due to the presence of similar manifestation in other IgA related disorders, such as IgA nephropathy (IgAN), ANCA-associated vasculitis overlap syndrome, IgA-dominant post-infectious glomerulonephritis, IgAvariant Goodpasture's syndrome and IgA-producing monoclonal gammopathy [40][41][42].
Twelve of twenty-three children were screened for ANCA: 11 were negative and one was c-ANCA negative but p-ANCA positive (this patient had IgA deposition in kidney biopsy but the possibility of concurrent ANCA-associated vasculitis could not be excluded at all). Eleven of twenty-three children were not screened for ANCA: six of them did not perform kidney biopsy, three had IgA deposition in renal biopsy, two had other glomerular pattern with different deposits in biopsy. Almost all children had a normal complement screening  Oral steroid then methylprednisolone iv.
In the majority of the cases, the pulmonary symptoms included cough, hemoptysis, epistaxis, dyspnea, tachypnea, chest pain and shortness of breath through to acute respiratory failure [8, 10, 14, 15, 23, 25-27, 30-35, 37-39]. However, pulmonary hemorrhage should be considered also in HSP patients with no respiratory symptoms or with common pulmonary manifestations. Two of twenty-three patients had no respiratory symptoms, but only radiological imaging findings suggestive of DAH [29,36]. So most but not all children with pulmonary vasculitis have respiratory symptoms, in some anemia or incidental radiological findings bring it to attention.
The time between the onset of the disease and the occurrence of the respiratory symptoms ranged from 2 days to 3 weeks, with a mean of 12 days [8, 10, 14, 15, 23, 25-27, 30-35, 37, 38], except for 2 cases in which the timing was not reported due to the absence of these symptoms [29,36].
The chest x-ray (CXR) was the first diagnostic step for DAH, and in most cases showed a pattern of diffuse bilateral pulmonary infiltrates.
In some cases, due to a misinterpretation of the CXR findings, patients were treated with antibiotic therapy due to a suspicion of a lobar pneumonia instead of DAH [10,27,37]. For this reason, bronchoalveolar lavage (BAL) should be performed to confirm diagnosis and start treatment promptly. Five of twenty-three children had BAL performed; the typical findings ranged from the evidence of blood in the alveolar space in the acute phase, to the presence of hemosiderin-laden macrophages in chronic hemorrhage [14,27,35,37,43].
The two patients without respiratory symptoms achieved DAH resolution, in one case with oral prednisone therapy alone and in the other with oral prednisone plus azathioprine [29,36]. Four children with DAH died despite treatment [8,10,23,25]. In the remaining 17 surviving patients (73%), at the time of pulmonary involvement, nine had required no therapy, three were being treated with oral prednisone and five with intravenous pulse methylprednisolone (due to the worsening of the kidney disease or to the massive lung involvement on the computed tomography scan).
Of the nine patients who had not been prescribed any medication, five of them needed mechanical ventilation and all of them achieved resolution with pulse methylprednisolone or with steroid treatment plus immunosuppressive therapy [10,[30][31][32][36][37][38].
The three patients treated with oral prednisone did not need intubation and all survived after receiving pulse methylprednisolone with or without another immunosuppressive drug (cyclophosphamide) [14,15,27].
Of the five patients who were administered pulse methylprednisolone, all of them needed mechanical ventilation, three of them continued with pulse methylprednisolone, and for the other two cyclophosphamide was added to the intravenous steroid [8,26,[33][34][35].
Before the onset of respiratory symptoms, 12 of the 17 children were not taking any medication or were on oral prednisone (2 mg/kg/day), which could suggest that oral steroid (and not intravenous steroid) seems not to prevent pulmonary involvement. However, those patients on oral steroid therapy did not need mechanical ventilation. The absence of medication increased the risk of acute respiratory failure, so steroid therapy was recommended to avoid intubation and to reduce the mortality rate [14,15,27].
No standard therapy was established for patients with HSP with pulmonary involvement; however, the first choice treatment was high-dose intravenous pulse methylprednisolone, with or without immunosuppressive therapy. Oral steroid therapy was ineffective for the prevention of lung involvement, considering that most patients were on oral steroids before the onset of DAH, although it did reduce the risk of acute respiratory failure [14,19,36].

Discussion and conclusion
HSP is one of the most common small-vessel vasculitis in children. It is generally a self-limiting disease in which the most feared complication is renal involvement.
Although rare, lung involvement in patients with HSP could be asymptomatic and should be investigated in order to diagnose potential lung involvement, due to a disease progression to a more severe clinical presentation, such as DAH. TLCO could be performed early in patients with HSP to evaluate the presence of pulmonary involvement even in the absence of symptoms, in order to perform more investigations and to begin the appropriate supportive treatment immediately. Indeed the carbon monoxide diffusing capacity tests is lower in children with HSP during the acute phase of the disease and normal during resolution of the disease.
In patients with DAH, the most common clinical findings are cough, hemoptysis, epistaxis, dyspnea, tachypnea, chest pain and shortness of breath through to acute respiratory failure that could require intubation and mechanical ventilation. Limited data are available for the prevention and treatment of lung involvement in HSP. It was observed that oral corticosteroids are not sufficient for the prevention of DAH, but they could reduce the need for mechanical ventilation. No guidelines regarding the treatment of DAH are so far available. Because of the disease progression and the common associated renal involvement, we suggest to treat every pulmonary complication with intravenous methylprednisolone, avoiding to wait an eventually life threatening complication as DAH. However, the best treatment for lung involvement in HSP is still a matter of debate and needs further researches.
Immunosuppressive treatment (azathioprine or cyclophosphamide) is indicated in presence of respiratory failure.
The limits of our article are that it is a narrative review and it is based almost on case reports or small case series. So, further multicentre studies on lung involvement in HSP are essential in order to define a diagnostic protocol, the best therapeutic strategies and their duration and the long-term outcomes.