Introduction

Idiopathic systemic capillary leak syndrome, first reported in 1960 by Bayard Clarkson and colleagues [3], and often referred to as Clarkson syndrome, is an unexplained condition characterized by episodes of acute increase in vascular permeability resulting in loss of protein-rich fluid into the interstitial compartment [30]. Episodes of the syndrome are often preceded by an acute intercurrent illness, present with the extravasation phase (which includes a first oligosymptomatic stage and a second polysymptomatic stage), characterized by peripheral edema and hypovolemia, and end in the recovery phase, characterized by the normalization of vascular permeability [30].

Clarkson syndrome has been diagnosed mainly in middle-aged adults with a monoclonal gammopathy [30]. Stimulated by our experience with a girl affected by this condition [21], we conducted a systematic review of the pediatric literature. The main questions were to document the preceding triggers, the clinical features, and the prognosis in children affected by Clarkson syndrome. The recently proposed treatment recommendations for these patients are also shortly discussed.

Methods

Between December 2017 and March 2018, we performed a search with no date limits of the Medical Subject Headings terms “idiopathic capillary leak” OR “Clarkson disease” OR “Clarkson syndrome” OR “primary capillary leak” OR “hyperpermeability capillary syndrome” in the US National Library of Medicine and Excerpta Medica databases. In an effort to detect all relevant secondary references, the literature of each included article and co-authors’ personal files were screened. The review was performed according to the Economic and Social Research Council guidance on the conduct of narrative synthesis and on the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement [22].

We selected only articles reporting cases of Clarkson syndrome (with or without monoclonal gammopathy) initially presenting in subjects ≤ 18 years of age. Reports published in Dutch, English, French, German, Italian, Portuguese, or Spanish were eligible, while articles in other languages were not considered. When more than one paper reported on the same patient, only the more comprehensive publication was retained. Patients affected by pre-existing conditions that have been associated with capillary leak such as adverse drug reactions, anaphylaxis, cancer, postoperative course, pregnancy, systemic inflammatory response syndrome, traumatic injuries, or kidney diseases, were excluded [30].

The diagnosis of Clarkson syndrome was made in children with acute onset of (i) peripheral edema; (ii) signs of tissue hypoperfusion including tendency to cool extremities, delayed capillary refill time, high heart and respiratory rate, weak pulses, or low blood pressure [4]; (iii) increase in the proportion of formed elements in the blood (hemoconcentration); and (iv) low blood protein level (total hypoproteinemia, hypoalbuminemia, or both) without any alternative explanation [30].

Episodes characterized by uncompensated shock (with or without acute kidney injury), muscle compartment syndrome, need for ventilatory support, or death were defined as severe.

From each reported case, following 10 data were sought: (1) gender, (2) age, (3) pre-existing conditions, (4) acute intercurrent illnesses preceding the extravasation phase by ≤ 7 days, (5) edema, (6) hemodynamic parameters (including shock), (7) laboratory data (including acute kidney injury and search for a monoclonal gammopathy), (8) rhabdomyolysis (with or without compartment syndrome), (9) management, and (10) number of episodes. In various instances, authors of published reports were also asked to provide additional missing data. The completeness of reporting was graded, according to the number of the aforementioned 10 items that were clearly reported, as high (≥ 8 items), satisfactory (5 to 7 items), or low (< 5 items). Acute kidney injury was categorized as stage I, II, or III according to the KDIGO classification [19].

Literature search, report selection, and data extraction were independently performed by two investigators (MAB, SAGL). Disagreements were resolved by consensus or adjudicated by a senior author (MGB). The Cohen’s kappa index was utilized to assess the agreement between investigators in applying inclusion and exclusion criteria. Results are given either as frequency or as median and interquartile range, as appropriate. Proportions were compared with the Fisher exact test, continuous variables with the Mann-Whitney-Wilcoxon test. Statistical significance was assigned at p < 0.05.

Results

Search results

The literature search process is summarized in Fig. 1. The chance-adjusted agreement between the two investigators on the application of the inclusion and exclusion criteria was 0.87. For the final analysis, we retained 24 scientific reports published since 1989 [1, 2, 5, 6, 8, 10,11,12,13,14,15,16,17, 20, 21, 23,24,25,26,27, 29, 31, 32, 34]: 9 from Europe (France, N = 3; Israel, N = 2; Italy, N = 2; Czech Republic, N = 1; Slovenia, N = 1), 9 from North America (USA, N = 6; Canada, N = 3), 5 from Asia (Turkey, N = 2; India, N = 1; Lebanon, N = 1; Japan, N = 1), and 1 from Australia. Twenty-three reports were published in English [1, 2, 5, 6, 8, 10,11,12,13,14,15,16,17, 21, 23,24,25,26,27, 29, 31, 32, 34] and one in French [20]. Completeness of reporting was high in 12, satisfactory in 8, and low in 4 articles.

Fig. 1
figure 1

Idiopathic systemic capillary leak syndrome (Clarkson syndrome) in childhood. Flowchart of the literature search process. The case of a patient reported on two occasions was counted only once

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Findings

The aforementioned 24 reports provided data on 32 otherwise healthy children, who presented with edema (pitting and non-itching in all but one case), signs of tissue hypoperfusion, hemoconcentration, and low blood protein level (Table 1). The condition affected more frequently girls than boys, initially presented throughout childhood, and was preceded by an acute illness in 75% of the cases. A monoclonal gammopathy was never detected. Ten patients experienced a single episode of capillary leak. The remaining 22 patients developed two or more episodes.

Table 1 Characteristics of 32 pediatric patients with Clarkson syndrome reported in the literature. Results are given either as median and interquartile range or as absolute number and percentage
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Sixty-seven episodes were rather well documented (Table 2). Uncompensated circulatory shock (with or without secondary cardiac arrhythmias), rhabdomyolysis (with or without compartment syndrome), acute kidney injury, pulmonary edema, and either pleural or pericardial effusion were, in decreasing order of frequency, the most common complications. Out of the 14 episodes of pulmonary edema, only 3 also had suffered from acute kidney injury. Both newborn infants [14, 17], an 8-year-old girl [11] and a 12-year-old boy [27], died during the acute phases of the disease. Interestingly, Clarkson syndrome concurrently affected one of these two newborns and its mother [14]. Forty (60%) of the 67 episodes were severe. Severe and not-severe episodes did not significantly differ with respect to age and sex.

Table 2 Complications of 67 rather well-documented episodes in pediatric patients affected by Clarkson syndrome
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Following microorganisms were detected in 15 cases of Clarkson syndrome preceded by an acute intercurrent illness: Influenzavirus (type A, N = 6; type B, N = 1), Parainfluenzavirus (type 1, N = 1; type 3, N = 1), Enteroviruses (N = 3), Respiratory syncytial virus (N = 1), Rotavirus (N = 1), and group A Streptococcus (N = 1).

Intravenous hydration, with or without inotropics, and 02-therapy were provided in almost all episodes. The remaining treatment options that were used in the 67 mentioned episodes of Clarkson syndrome are depicted in Table 3. Ventilatory support was provided in 19 (including extra corporeal membrane oxygenation in one case) and cardiorespiratory resuscitation in 5 episodes. Fifteen patients were prescribed various agents on a long-term basis in order to prevent recurrences.

Table 3 Treatment options other than intravenous hydration or inotropics and prophylactic management in pediatric subjects with Clarkson syndrome. Information on treatment options was available for 67 episodes. Information on prophylactic management was available for 15 subjects. More than one treatment strategy or prophylactic management were applied in some cases
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Discussion

Approximately 500 cases of Clarkson syndrome have been reported worldwide, primarily in middle-aged adults with a monoclonal gammopathy [2, 30]. This comprehensive literature review documents 32 pediatric cases of Clarkson syndrome. Like in adults, childhood Clarkson syndrome is an acute non-familial condition that is life-threatening and tends to recur. Childhood Clarkson syndrome affects newborns, infants, toddlers, preschoolers, and especially schoolers and is very often preceded by an acute mostly viral intercurrent illness and is not linked to a monoclonal gammopathy.

The initial oligosymptomatic extravasation stage [2, 30] is characterized by non-specific (such as fatigue, irritability, abdominal pain, vomiting, diarrhea, nausea, and aches) and more specific symptoms and signs (such as polydipsia, and increase in body weight) during 1 to 4 days. It is followed by the polysymptomatic extravasation stage, which is characterized by peripheral edema and signs of tissue hypoperfusion such as cool extremities, delayed capillary refill time, high heart and respiratory rate, weak pulse, and a tendency to low blood pressure and is often complicated by uncompensated circulatory shock, signs of end-organ ischemia including acute kidney injury, muscle compartment syndrome, and pleural or pericardial effusion [2, 30]. Finally, during the recovery phase, which results from the normalization of vascular permeability, extravasated fluids are recruited back into the intravascular space with subsequent volume overload and risk of pulmonary edema [2, 30].

The mechanisms underlying Clarkson syndrome are still elusive. The vast majority of affected adults have a detectable monoclonal protein in blood, but this pediatric survey supports the assumption that the monoclonal protein does not play a pivotal pathogenic role. Multiple cytokines are elevated in blood of these patients [2, 12, 30]. Furthermore, serum from the affected patients induces hyperpermeability in human endothelial cells, suggesting that a soluble factor is pathogenically crucial [2]. The Clarkson case concurrently affecting both a newborn baby and its mother suggests that the factor may be transferred from the mother to the fetus [14]. Similar mechanisms underlie various neonatal diseases such as alloimmune hemolytic anemia or thrombocytopenia of the newborn, neonatal hyperthyroidism, neonatal myasthenia, neonatal systemic lupus erythematosus [7], and transient nephrotic syndrome [33]. The vascular dysfunction in Clarkson syndrome shares similarities with that seen in Ebola and Marburg hemorrhagic fevers [30]. Interestingly, Ebolavirus, Marburgvirus, and all the viruses documented in childhood Clarkson syndrome (Influenzavirus, Parainfluenzavirus, Enteroviruses, Respiratory syncytial virus, and Rotavirus) are RNA viruses [30].

The challenging diagnosis of Clarkson syndrome deserves consideration in previously otherwise healthy children with acute onset of pitting and non-itching peripheral edema associated with the “3 Hs” triad of tissue Hypoperfusion, Hemoconcentration, and either total Hypoproteinemia or Hypoalbuminemia. In these patients, “allergic” findings such as hives, tongue or perioral swelling, wheezing, or stridor are not observed and urinalysis does not disclose a significant proteinuria [2, 30].

Like further cases of hypovolemic shock, acute episodes should be managed with intravenous crystalloids, inotropic agents and supplemental O2. Intubation and mechanical ventilation may be required to relieve an increased work of breathing. In particular, clinicians should be watching for the development of an anterior tibial compartment syndrome, which may be exacerbated by fluid resuscitation.

The transition from the extravasation to the recovery phase should be appreciated thank to a decrease in the volume of intravenous fluids required to maintain adequate perfusion. When this occurs, the treatment focus should shift to the prevention of intravascular volume overload and its complications. During this phase, many patients require diuretics to avoid volume overload with subsequent pulmonary edema.

There are no randomized trials to guide the prevention of this condition. Rather, recommendations rest on single-patient reports, observational studies, and consensus statements. Long-term prophylaxis with (a) an oral combination of the β2-adrenergic agonist terbutaline and a methylxanthine and especially (b) parenteral polyclonal immunoglobulins appears to be beneficial [2, 9, 12, 18, 28]. Furthermore, affected subjects should be encouraged to seek medical care whenever they recognize initial symptoms because early administration of immunoglobulins might be helpful [2, 9, 12, 18, 28].

Three main limitations of this work should be acknowledged. First, results must be viewed with an understanding of the inherent limitations of the analysis process, which incorporated data from case reports that were sometimes poorly documented. Second, the number of published cases is small. Third, available data do not allow to appraise the difference between pediatric and adult Clarkson’s patients.

In conclusion, this survey points out that Clarkson syndrome develops not only in adulthood but also in childhood. In this age group, this condition is not linked to a monoclonal gammopathy.