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Part I: Retiform Purpura: A Diagnostic Approach
Journal Pre-proof Part I: Retiform Purpura: A Diagnostic Approach Corey Georgesen, MD, Lindy P. Fox, MD, Joanna Harp, MD PII:
S0190-9622(19)32672-6
DOI:
https://doi.org/10.1016/j.jaad.2019.07.112
Reference:
YMJD 13788
To appear in:
Journal of the American Academy of Dermatology
Received Date: 9 May 2019 Revised Date:
15 July 2019
Accepted Date: 28 July 2019
Please cite this article as: Georgesen C, Fox LP, Harp J, Part I: Retiform Purpura: A Diagnostic Approach, Journal of the American Academy of Dermatology (2019), doi: https://doi.org/10.1016/ j.jaad.2019.07.112. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
Part I: Retiform Purpura: A Diagnostic Approach Corey Georgesen, MD1; Lindy P. Fox, MD2; Joanna Harp, MD3 1. University of Pittsburgh Medical Center, Dept. of Dermatology 2. University of California, San Francisco, Dept. of Dermatology 3. Weill Cornell Medicine, Dept. of Dermatology
Correspondence: Corey Georgesen, MD UPMC Dermatology 9000 Brooktree Rd, Suite 200 Wexford, PA, 15090 Fax: 724-933-1338 [email protected]
Word and Figure Count: Part I: 2,819 words; 12 Figures, 1 Table All authors have approved the manuscript in its final form, and we have no conflicts of interest nor financial obligations to disclose.
Retiform purpura is a specific morphology within the spectrum of reticulate eruptions of vascular origin. This morpology develops when blood vessels serving the skin are compromised resulting in downstream cutaneous ischemia, purpura, and necrosis. Blood vessel compromise occurs by one of two mechanisms, 1) vessel wall damage (vasculitis/depositional disease/angioinvasion by organism) or 2) vessel lumen occlusion (thrombotic or embolic disease). Understanding the mechanisms that lead to retiform purpura helps inform the differential diagnosis.1-3
Recognition of retiform purpura is paramount, especially in the acute or severely ill patient, as it may elucidate the underlying diagnosis, provide prognostic information, and suggest a treatment approach. The differential diagnosis of retiform purpura is vast, reflecting the myriad conditions that can lead to cutaneous vessel wall damage or lumen occlusion. For example, a patient with bacterial sepsis may develop direct bacterial angioinvasion, reactive leukocytoclastic vasculitis, bacterial vaso-occlusive emboli, and/or disseminated intravascular coagulation, all of which can present with retiform purpura, although each through a distinct mechanism. Herein we describe an overview of the differential diagnosis of this cutaneous morphology, provide an approach to workup, and highlight updates in treatment of some of the more common conditions that manifest as retiform purpura.
2
We suggest the following clinical approach to the patient with retiform purpura: 1) What is the morphology of the lesion? 2) What is the status of the patient? 3) What is the location of the lesion? 4) What is the patient’s past medical and family history? 5) Are there any pertinent positives on review of systems? 6) Are there any additional relevant physical exam findings?
This six-step approach is designed to guide the clinician towards a narrowed differential diagnosis based on patient history and physical exam. However, it is important to note that most (if not all) patients with new onset retiform purpura warrant a skin biopsy and laboratory workup.
Step One. Morphology of the lesion. •
Retiform purpura refers to a distinct clinical morphology.
•
The differential diagnosis consists of pathophysiology centered on either the vessel lumen or the vessel wall.
First, what does retiform purpura mean from a morphologic perspective? These lesions present with a branching (reticular), non-blanching (purpuric) patch or plaque, which can occur anywhere on the body or mucous membranes.3 Lesions of retiform purpura are persistent and often accompanied by frank or impending central necrosis and/or ulceration. This contrasts with
3
other reticulate eruptions of vascular etiology including livedo reticularis and livedo racemosa. Livedo reticularis4 results from only partial or intermittent reduction of cutaneous blood flow leading to non-fixed, dusky patches forming complete rings reflecting the underlying cutaneous vasculature. (Figure 1A) Livedo racemosa, which is representative of a more irregular and significant reduction of blood flow, presents with broken rings that are persistent but rarely necrotic or ulcerative.5 (Figure 1B)
Unlike livedo, retiform purpura does not display the net-like pattern of rings, but instead displays branching at the periphery of a purpuric or necrotic center. Some authors have described it as “river-like” or “serpentine purpura,” and others note that the lesions may appear as “puzzle pieces” of livedo fit together.3 Lesions may be exquisitely painful reflecting the complete obstruction of blood flow to the skin with resultant ischemia and necrosis.2 We have provided representative lesions of retiform purpura (Figure 1A-D) to display the varied clinical presentation of these lesions. With experience and pattern recognition, these lesions are often immediately obvious.
Figures 2 summarizes the differential diagnosis of retiform purpura. When considering this vast differential, we find that it is helpful to first consider (and then confirm with skin biopsy) whether the disease pathology is within the vessel wall or the vessel lumen. If the disease centers on the vessel wall, the differential diagnosis includes depositional diseases (such as calciphylaxis6), angioinvasive organisms and vasculitides. While palpable purpura is the classic manifestation of small vessel vasculitis, concomitant retiform purpura indicates that a medium vessel component is also present. Thus, purely medium vessel vasculitides such as polyarteritis
4
nodosa7, in addition to small and medium mixed vessel vasculitides such as IgA vasculitis8 and cryoglobulinemia9, can occasionally present with retiform purpura, though this is not the most common presentation. On the other hand, if cutaneous histology reveals blockage of the vessel lumen, the differential diagnosis centers upon thromboembolic processes. Occlusion of cutaneous blood vessels can occur through a wide variety of mechanisms including hypercoaguable states (antiphospholipid syndrome10, disseminated intravascular coagulation, genetic disorders), platelet plugging (thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), heparin induced thrombocytopenia (HIT)), elevated or dysfunctional red and white blood cells (polycythemia vera, sickle cell anemia, intravascular lymphoma), temperature-related processes (cryoglobulinemia11, cryofibrinogenemia), and finally embolic processes (septic, cholesterol, marantic). (Figure 23,5,12-14)
In an effort to narrow this wide differential diagnosis, some authors have recommended categorizing lesions as either “inflammatory” retiform purpura, or “non-inflammatory” retiform purpura.2-3 “Inflammatory” retiform purpura refers to the clinical presence of erythema around the lesion (accounting for a minimum of 2/3 of the lesion) with ≤ 1/3 of the lesion accounted for by central impending necrosis. “Inflammatory” retiform purpura suggests a vasculitic or infectious process. “Non-inflammatory” retiform purpura2-3 refers to clinical lesions presenting with 2/3 central frank or impending necrosis and ≤ 1/3 surrounding erythema and suggests an occlusive process. While this clinical categorization can be helpful in many cases, it is important to note that significant overlap exists. In addition, a few select diseases, i.e. cryoglobulinema, sepsis, and levamisole associated retiform purpura, may have both vasculitic and thrombotic pathophysiologic components. Therefore, while the degree of inflammation may be suggestive, a
5
strategized laboratory and pathologic evaluation (as detailed in subsequent sections of this manuscript) is necessary in all cases.
A final helpful clue when inspecting the morphology is the perceived acuity of the lesion. In a patient with multiple lesions of varying stages with atrophie blanche-like scarring of older lesions, one might surmise that skin lesions are resultant from a chronic, smoldering, intermittent process such as liveoid vasculopathy18. (Figure 3) In contrast, a patient with new onset of many lesions, all in a similar stage of development, may suggest a more acute, active process such as purpura fulminans (Figure 4) or a medication induced processes such as warfarin induced skin necrosis or hepatin induced thrombocytopenia.2,5,19 (Figure 5)
Step Two. Status of patient. •
Acute retiform purpura in a sick patient should prompt a search for serious and reversible causes.
•
It may be appropriate to send an initial battery of tests while awaiting skin biopsy results.
The next checkpoint is straightforward yet crucial. The clinician should briefly pause to consider the overall health of the patient. If, for example, the patient is severely ill, the clinician must first and foremost consider rapidly progressive, potentially fatal, and reversible causes. In many cases, this will mean proceeding with an initial battery of tests and urgent skin biopsy prior to moving any further in this diagnostic six-step algorithm.
6
In the emergent setting, when the patient presents with retiform purpura, fever, altered mental status, organ failure, and/or septic shock, we suggest a workup as outlined in Figure 620-30. Of course, workup should be discussed and followed with the intensivists, internists, and appropriate consultants. The dermatologist should pursue an immediate skin biopsy for hematoxylin and eosin (H&E) and tissue culture and direct immunofluorescence when appropriate. In the patient with systemic infection, tissue culture from the skin may identify the offending organism and provide antimicrobial sensitivity data. Broad-spectrum antibacterial and antifungal coverage should be initiated in septic or immunocompromised patients while awaiting results. The clinician should review the patient’s labs including platelet count and coagulation studies to evaluate for evidence of disseminated intravascular coagulation (DIC). Review of medications should be rapidly undertaken to identify if the patient is on any high-risk medications (newly started heparin or warfarin or drugs that can cause ANCA+ vasculitis) that may need to be held or changed while work up is underway.
Step Three. Lesion Location. •
Certain items on the differential diagnosis have characteristic anatomic locations.
•
Disseminated retiform purpura can encompass both infectious and non-infectious causes.
7
The anatomic distribution of retiform purpura can guide the clinician. (Figure 7) Some locations are classic, such as the free cartilage of the ear in levamisole-induced purpura31-32 (Figure 8) and peri-umbilical “thumbprint” purpura in disseminated strongyloides.33
Acral retiform purpura, especially on distal areas of the fingers and toes, should alert the clinician toward a possible embolic cause or cold-associated disease. Acral lesions (retiform purpura or a purpuric digit) accompanied by a recent cardiac procedure and an elevated eosinophil count suggest cholesterol emboli.34 (Figure 9) Patients with acral lesions and sepsis should be examined for cutaneous findings of endocarditis, including splinter hemorrhages, Janeway lesions (nontender, small petechiae on the palms and soles), and Osler nodes (painful erythematous papules), and an echocardiogram should be considered.35-36 In a patient with a history of systemic lupus, non-infective (marantic) endocarditis should be ruled out.37 Cryoglobulinemia (type I occlusive disease in the setting of myeloproliferative diseases and types II and III associated with cutaneous vasculitis) favors acral areas, including the ears and the nose, where body temperatures are lower.12
In lesions occurring predominantly on the lower extremities, vasculitides may be higher on the differential (especially if seen in conjunction with palpable purpura). If patients present with small punched out ulcerations and atrophie blanche (indicating chronicity) on the shins and dorsal feet, with a background of livedo, consider livedoid vascuopathy. In patients from Mexico and the Caribbean with lepromatous leprosy, an additional consideration would be the Lucio phenomenon.38-39
8
Purpuric lesions occurring on fatty areas of the abdomen and thighs might suggest warfarin or heparin induced skin necrosis. Warfarin induced skin necrosis classically starts within the first ten days of warfarin initiation (most often on days 3-5), when protein C levels hit nadir, and often occurs on the abdomen, thighs, buttocks, and breasts.5
Ecthyma gangrenosum40 and meningococcemia5,41 may present with acute disseminated lesions. In the setting of acute widespread purpura without an infectious source, catastrophic antiphospholipid syndrome, purpura fulminans, and calciphylaxis42 (uremic or non-uremic) should be considered.
Step Four. Medical and Family History. •
Next collect relevant medical and family history.
•
Use previous clues for guidance.
For all patients with retiform purpura, we suggest thinking through the following set of general medical and family history questions, which should be specifically tailored to the location and acuity of the lesions:
1) Does the patient have any relevant personal or family history? a. End stage renal disease is associated with calciphylaxis.9 b. Connective tissue disease can be associated with antiphospholipid syndrome. Additionally, small and medium vasculitis can be seen in the setting of Sjogren’s
9
syndrome and rheumatoid arthritis. Mixed cryoglobulinemia can be seen in the setting of rheumatoid arthritis and lupus.43 c. Previous history of cerebrovascular accident or spontaneous abortion may be indicative of the antiphospholipid syndrome.44 d. History of severe asthma or nasal polyposis as can be seen in eosinophilic granulomatosis with polyangitis.45-46 Ear, nose, and airway manifestations are also common presenting symptoms in polyangitis with granulomatosis.47 e. Hepatitis is associated with cryoglobulinemia type II and III5,43 and polyarteritis nodosa5. f. If history of malignancy, IgA (and/or leukemic vasculitis) should be considered.4855
g. History of hereditary hemoglobinopathies such as sickle cell disease, thalassemia, and spherocytosis must be asked. h. A family history of myeloproliferative disorders would highlight a tendency towards a hematologic disease that may present with cryoglobulinemia56. 2) Does the patient have any recent or active infections? a. Disseminated intravascular coagulation and purpura fulminans can occur in the setting of various infections, especially encapsulated Gram positive bacteria.2,5,57 b. Ecthyma gangrenosum is associated with Gram negative sepsis. c. Hemolytic uremic syndrome has been associated with Shiga-toxin producing E. Coli, pneumococcus, and influenza, among others.58 d. Cold agglutinins are associated with infections, most commonly Mycoplasma pneumoniae.59
10
e. Cutaneous polyarteritis nodosa is commonly associated with streptococcal infection.5,10 f. Streptococcal and upper respiratory viral infections are associated with IgA vasculitis (Henoch Schonlein purpura).60 g. Angioinvasive fungal infections typically present in severely immunocompromised patients with signs of infection but who are not responding to broad antibiotic coverage. 3) Has the patient started any new medications or had exposure to illicit drugs? a. Warfarin induced necrosis and heparin induced thrombocytopenia most often occur within the first 3-5 and 7-10 days of initiation, respectively5 b. Certain medications, most commonly tumor necrosis factor (TNF) inhibitors, propylthiouracil, hydralazine, minocycline, rituximab, and statins, among many others, have been implicated in drug induced vasculitis.61 c. Levamisole contaminated cocaine is associated with retiform purpura classically of the ears and acral areas.31-32 4) Has the patient undergone recent instrumentation? a. Embolization, most notably cholesterol emboli, are commonly associated with cardiac procedures.34
Step Five. Review of systems. •
Review of systems should be tailored toward the patient.
•
Cutaneous vasculitis necessitates a search for systemic involvement.
11
A comprehensive review of systems for the patient presenting with retiform purpura can be found in Table 12,3,5, 15-17, 19, 43, 62-67. However, it must be emphasized that the review of systems can (and should) be focused on entities highest on the differential diagnosis. For example, in the patient with retiform purpura and deep vein thrombosis, be sure to ask about pulmonary symptoms given concern for pulmonary embolism. In the patient from an endemic area, consider strongyloides and ask about malaise, fatigue, and pulmonary or gastrointestinal symptoms. In the patient with streptococcal infection, ask about abdominal pain, joint pain, and change in urine color.
Finally, whenever vasculitis is suspected, systemic involvement must be ruled out with the review of systems, in addition to the physical exam and laboratory workup. Systems affected by the various vasculidites include: neurologic (cerebrovascular accident, mononeuritis multiplex), ocular, head and neck (epistaxis, sinusitis), pulmonary (hemoptysis or chest pain), cardiac (chest pain), abdominal (pain, diarrhea, melena), musculoskeletal (arthralgia), and renal (change in urine color).2,7,17,43,63
Step Six. Associated Physical Exam Findings. •
Thorough physical examination is requisite in patients with retiform purpura.
•
Full skin examination is important as obscured areas can have diagnostic clues.
12
As outlined, previous steps in this diagnostic algorithm involve assessing lesion morphology, degree of inflammation, and location. A full physical examination is also essential to fully evaluate the patient who presents with retiform purpura. The heart and lung examination as performed by the intensivist should be reviewed for associated findings (the murmur of bacterial endocarditis, friction rub of pericarditis, rales of interstitial lung disease, etc.) A musculoskeletal exam should be performed. Muscles strength should be assessed with an emphasis on the pelvic and shoulder girdles. Careful palpation for lymphadenopathy should be performed.68-70
The final step in the diagnostic algorithm is a complete and thorough skin examination. A myriad cutaneous exam findings can give support to the suspected diagnosis.
Going (anatomically) from top to bottom, the physician should start in the scalp, looking for any sign of scarring alopecia as may be associated with connective tissue disease. The conchal bowls can be examined for signs of chronic cutaneous lupus. All mucous membranes should be inspected. Conjunctival hemorrhage can be suggestive of a platelet diathesis or disseminated intravascular coagulation.71 The nares deserve inspection, as nasal polyps and angioinvasive fungi (mucormycosis) can be obvious without endoscopy. The oral mucosa should be carefully examined for signs of ulceration, purpura, or xerostomia. Additionally, the clinician can look for the strawberry gingivitis of polyangitis with granulomatosis.72-75
The dermatologist should perform a full skin exam of the trunk, extremities, and genitals. The patient should be repositioned when necessary to observe obscured areas. No area should be neglected; areas under chest leads, adhesives, and surrounding I.V. sites must be examined, as
13
diagnostic lesions may otherwise remain concealed. (Figure 10) These are also potential sites of inoculation of invasive fungal organisms in the immunosuppressed hospitalized patient.
Finally, the nails deserve close inspection. Koilonychia, or spoon nails, can be observed in anemia that is associated with malignancy, autoimmune, or other chronic disease.76 Lindsay’s nails, or half and half nails, may be associated with chronic renal disease.77 Terry’s nails are associated with cirrhosis as can be seen in hepatitis C.78 Muehrcke’s nails, which present as parallel lines of blanchable leukonychia (pathology of the nail bed), are associated with low protein states such as nephrotic syndrome or liver disease.79 The proximal nailfold should be inspected for the presence of vascular dropout, meandering and dilated vessels, or frayed cuticles (Samitz sign80), which can signify the presence of autoimmune connective tissue disease.81-83 Finally, in the immunocompromised patient, nails should be inspected for inflammation and subungual discoloration, as fusarium and other angioinvasive organisms can disseminate from a primary cutaneous paronychia or onychomycosis.84-85
Completing the Workup •
Biopsy location should be selected to maximize probability of capturing representative pathology.
•
Laboratory evaluation will vary and is dependent upon previous steps detailed in the diagnostic algorithm.
14
Now the clinician is prepared to complete the diagnostic workup by performing a biopsy for H&E (plus tissue culture and/or direct immunofluorescence as deemed appropriate) and collecting laboratory data.
Biopsy should be collected at the peripheral purpuric rim of the lesion. When hemorrhagic bullae are present, as is often the case in bacterial and fungal sepsis, fluid can be obtained for bacterial culture and the blister roof should be scraped for potassium hydroxide examination. In other cases, biopsy specimens can be smeared on a glass slide for touch preparation, as described by other authors.86 Finally, in patients with suspected infection, consider obtaining a second biopsy from the necrotic center for tissue culture.87
The differential diagnosis of retiform purpura informs the laboratory evaluation. The extent and timing of laboratory work up will vary depending on the acuity of the skin manifestations, the overall health of the patient, and any relevant history and physical exam findings that may narrow the differential. If the patient is severely or acutely ill, it may be reasonable to send many tests immediately to try to narrow the differential while biopsy results are pending. If skin lesions are more chronic and/or stable, it may be preferable to await biopsy results, confirm if the pathology is in the vessel wall or lumen, and then work through the evaluation based on a narrowed differential diagnosis. Retiform purpura laboratory evaluation is detailed in Figure 113,5,15-17, 19,22,27,34,4363-64,88.
Prompt treatment should follow. Part II of this CME will detail these steps in relation to four of the most common causes of retiform purpura.
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53. Mifune D, Watanabe S, Kondo R, Wada Y, Moriyama H, Kagamu H, Yoshizawa H, Tetsuka T, Matsuyama A, Ito K, Narita I. Henoch Schönlein purpura associated with pulmonary adenocarcinoma. J Med Case Rep. 2011 Jun 22;5:226.
54. Akizue N, Suzuki E, Yokoyama M, Inoue M, Wakamatsu T, Saito T, Kusakabe Y, Ogasawara S, Ooka Y, Tawada A, Maru Y, Matsue H, Chiba T. Henoch-Schönlein Purpura Complicated by Hepatocellular Carcinoma. Intern Med. 2017 Nov 15;56(22):3041-3045.
55. Mifune D, Watanabe S, Kondo R, Wada Y, Moriyama H, Kagamu H, Yoshizawa H, Tetsuka T, Matsuyama A, Ito K, Narita I. Henoch Schönlein purpura associated with pulmonary adenocarcinoma. J Med Case Rep. 2011 Jun 22;5:226.
56. Platto J, Alexander CE, Kurtzman DJB. A Violaceous, Photodistributed Cutaneous Eruption and Leg Ulcer in a Woman With Essential Thrombocytosis. JAMA Dermatol. 2018 Jan 1;154(1):95-96.
57. Chalmers E, Cooper P, Forman K, Grimley C, Khair K, Minford A, Morgan M, Mumford AD. Purpura fulminans: recognition, diagnosis and management. Arch Dis Child. 2011 Nov;96(11):1066-71.
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58. Fakhouri F, Zuber J, Frémeaux-Bacchi V, Loirat C. Haemolytic uraemic syndrome. Lancet. 2017 Aug 12;390(10095):681-696.
59. de Groot RCA, Meyer Sauteur PM, Unger WWJ, van Rossum AMC. Things that could be Mycoplasma pneumoniae. J Infect. 2017 Jun;74 Suppl 1:S95-S100.
60. Farhadian JA, Castilla C, Shvartsbeyn M, Meehan SA, Neimann A, Pomeranz MK. IgA vasculitis (Henoch-Schönlein purpura). Dermatol Online J. 2015 Dec 16;21(12). pii: 13030/qt72p3m3q2.
61. Grau RG. Drug-Induced Vasculitis: New Insights and a Changing Lineup of Suspects. Curr Rheumatol Rep. 2015 Dec;17(12):71.
62. Micheletti RG, Werth VP. Small vessel vasculitis of the skin. Rheum Dis Clin North Am. 2015;41(1):21-32, vii.
63. Goeser MR, Laniosz V, Wetter DA. A practical approach to the diagnosis, evaluation, and management of cutaneous small-vessel vasculitis. Am J Clin Dermatol. 2014 Aug;15(4):299-306.
64. Batu ED, Ozen S. Vasculitis: do we know more to classify better? Pediatr Nephrol. 2015 Sep;30(9):1425-32.
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65. Reyhan I, Goldberg BR, Gottlieb BS. Common presentations of pediatric rheumatologic diseases: a generalist's guide. Curr Opin Pediatr. 2013 Jun;25(3):388-96.
66. Lisnevskaia L, Murphy G, Isenberg D. Systemic lupus erythematosus. Lancet. 2014 Nov 22;384(9957):1878-1888.
67. Yu C, Gershwin ME, Chang C. Diagnostic criteria for systemic lupus erythematosus: a critical review. J Autoimmun. 2014 Feb-Mar;48-49:10-3.
68. Woolf AD, Akesson K. Primer: history and examination in the assessment of musculoskeletal problems. Nat Clin Pract Rheumatol. 2008 Jan;4(1):26-33.
69. Kunzler E, Hynan LS, Chong BF. Autoimmune Diseases in Patients With Cutaneous Lupus Erythematosus. JAMA Dermatol. 2018 Jun 1;154(6):712-716.
70. Weetman AP, Walport MJ. The association of autoimmune thyroiditis with systemic lupus erythematosus. Br J Rheumatol. 1987 Oct;26(5):359-61.
71. Azar P, Smith RS, Greenberg MH. Ocular findings in disseminated intravascular coagulation. Am J Ophthalmol. 1974 Sep;78(3):493-6.
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72. Wawrzycka K, Szczeklik K, Darczuk D, Lipska W, Szczeklik W, Musiał J. Strawberry gingivitis as the first manifestation of granulomatosis with polyangiitis. Pol Arch Med Wewn. 2014;124(10):551-2.
73. Ghiasi M. Strawberry Gingivitis in Granulomatosis with Polyangiitis. N Engl J Med. 2017 Nov 23;377(21):2073.
74. van der Leeuw J, Flinsenberg TWH, Siezenga MA. Strawberry gingivitis as a manifestation of granulomatosis with polyangiitis. Rheumatology (Oxford). 2018 Feb 1;57(2):226.
75. Kumar RR, Jha S, Sharma A. Strawberry Gingivitis: A rare manifestation of granulomatosis with polyangiitis. QJM. 2018 Aug. doi: 10.1093/qjmed/hcy179. [Epub ahead of print]
76. Walker J, Baran R, Vélez N, Jellinek N. Koilonychia: an update on pathophysiology, differential diagnosis and clinical relevance. J Eur Acad Dermatol Venereol. 2016 Nov;30(11):1985-1991.
77. Gagnon AL, Desai T. Dermatological diseases in patients with chronic kidney disease. J Nephropathol. 2013 Apr;2(2):104-9.
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78. Witkowska AB, Jasterzbski TJ, Schwartz RA. Terry's Nails: A Sign of Systemic Disease. Indian J Dermatol. 2017 May-Jun;62(3):309-311.
79. Muerhrcke RC. The finger-nails in chronic hypoalbuminaemia; a new physical sign. Br Med J. 1956 Jun 9;1(4979):1327-8.
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81. Cortes S, Cutolo M. Capillarosecopic patterns in rheumatic diseases. Acta Reumatol Port. 2007 Jan-Mar;32(1):29-36.
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83. Hasegawa M. Dermoscopy findings of nail fold capillaries in connective tissue diseases. J Dermatol. 2011 Jan;38(1):66-70.
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87. Singer HM, Reddy BY, Grossman ME. Touch preparation for the rapid diagnosis of disseminated aspergillosis. JAAD Case Rep. 2017 Apr 14;3(3):202-204.
88. Galimberti R, Torre AC, Baztán MC, Rodriguez-Chiappetta F. Emerging systemic fungal infections. Clin Dermatol. 2012 Nov-Dec;30(6):633-50
29
Figure Legends.
Figure 1. (a) Livedo reticularis: Note the presence of complete rings. These are transient and often temperature related. (b) Livedo racemosa: Note the presence of broken, irregular, fixed rings.
Figure 2. Retiform purpura in a patient with (a) calciphylaxis, (b) septic vasculitis, (c) IgA vasculitis, and (d) disseminated intravascular coagulation
Figure 3. Differential diagnosis of retiform purpura based on pathophysiology.
Figure 4. Livedoid vasculopathy in a 39-year-old female with anti-phospholipid syndrome.
Figure 5. Pupura fulminans in presenting patients admitted to the intensive care unit.
Figure 6. Heparin induced thrombocytopenia-induced retiform purpura.
Figure 7. Workup for retiform purpura in the acutely ill patient.
Figure 8. Anatomic distribution of common causes of retiform purpura.
Figure 9. Levamisole-induced retiform purpura. (Photograph courtesy of Christine Ahn, MD).
30
Figure 10. Retiform purpura in the setting of cholesterol emboli following cardiac catheterization.
Figure 11. The “bullseye infarct” purpuric lesions of mucormycosis: A 6-year old with acute lymphoblastic leukemia presented with retiform purpura (a) next to an intravenous puncture site that evolved into a non-retiform purpuric plaque. A 52-year-old with in septic shock presents with a purpuric patch (c-d) under a chest lead. While not retiform in this photograph, systemic fungal infections can sometimes present with retiform lesions that quickly evolve into different morphologies.
Figure 12. Retiform purpura laboratory evaluation.
Table 1. Complete retiform purpura review of systems.
31
System
Symptom
General
fatigue weight changes
Associations
fever
connective tissue disease, leukemia/lymphoma, chronic infections (hepatitis, malaria, parasitic), endocarditis, anemia (sickle cell, paroxysmal nocturnal hemoglobinuria) malignancy, chronic infections connective tissue disease, leukemia/lymphoma, acute infection (bacterial, fungal), chronic infections (hepatitis, malaria, parasitic), endocarditis, ANCA vasculitis
conjunctival hemorrhage (red eye)
hemoglobinopathies, TTP, HUS, DIC, connective tissue disease
vision change
vasculitis (ANCA, leukemic, septic, cryoglobulinemia), infection (mucormycosis)
hearing change, tinnitus
vasculitis (ANCA, leukemic, septic, cryoglobulinemia)
Nose
epistaxis sinusitis
vasculitis (polyangitis with granulomatosis), thrombocytopenia (TTP, HUS, DIC) eosinophilic granulomatosis with polyangitis
Mouth
xerostomia recurrent ulcers
Sjogrens syndrome, connective tissue disease connective tissue disease
Neuro
headache
connective tissue disease (lupus), infection (meningococcemia, angioinvasive fungi), vasculitis, cryoglobulinemia
altered mental status numbness, loss of sensation loss of motor function seizure
infection (sepsis), TTP vasculitis (ANCA, polyarteritis nodosa), leprosy, cerebrovascular accident (antiphospholipid syndrome) vasculitis (ANCA, polyarteritis nodosa), leprosy, cerebrovascular accident (antiphospholipid syndrome) connective tissue disease (lupus)
Ocular
Ear
Respiratory
Cardiovascular
chest pain
connective tissue disease (pleuritis), hypercoagulative state (embolus)
shortness of breath hemoptysis
connective tissue disease (pulmonary hypertension, interstitial lung disease), hypercoagulative state (embolus), infection (endocarditis, pneumonia) infection (pneumonia), vasculitis (granulomatosis with polyangitis)
chest pain edema calf pain
connective tissue disease (carditis), cardiomyopathy (eosinophilic granulomatosis with polyangitis) renal disease (calciphylaxis), liver disease (cryoglobulinemia, IgA vasculitis),deep venous thrombosis (hypercoagulative state, antiphospholipid syndrome) deep venous thrombosis (hypercoagulative state, antiphospholipid syndrome)
appetite change
vasculitis (IgA, cryoglobulinemia, leukemic), bowel infarcation (hypercoagulable state, embolus, DIC), malignant atrophic papulosis vasculitis (IgA, cryoglobulinemia, leukemic) lymphoma (leukemic vasculitis, cryoglobulinemia, intravascular lymphoma), malignancy (IgA vasculitis), parasite (strongyloides)
jaundice/kernicterus
liver disease (cryoglobulinemia, IgA vasculitis)
Genitourinary
change in color dysuria
vasculitis (IgA, ANCA, cryoglobulinemia), connective tissue disease (lupus, systemic sclerosis), paroxysmal nocturnal hemoglobinuria infection (urosepsis)
Musculoskeletal
proximal weakness arthralgia
connective tissue disease (dermatomyositis) connective tissue disease (lupus, mixed connective tissue disease), cryoglobulinemia
Hematologic
ease of bruising
lymphoma (leukemic vasculitis, cryoglobulinemia, intravascular lymphoma), liver disease (cryoglobulinemia, IgA vasculitis), thrombocytopenia (TTP, HUS, DIC, HIT)
ease of bleeding
thrombocytopenia (TTP, HUS, DIC, HIT)
Gastrointestinal
pain melena
S0190-9622(19)32672-6
DOI:
https://doi.org/10.1016/j.jaad.2019.07.112
Reference:
YMJD 13788
To appear in:
Journal of the American Academy of Dermatology
Received Date: 9 May 2019 Revised Date:
15 July 2019
Accepted Date: 28 July 2019
Please cite this article as: Georgesen C, Fox LP, Harp J, Part I: Retiform Purpura: A Diagnostic Approach, Journal of the American Academy of Dermatology (2019), doi: https://doi.org/10.1016/ j.jaad.2019.07.112. This is a PDF file of an article that has undergone enhancements after acceptance, such as the addition of a cover page and metadata, and formatting for readability, but it is not yet the definitive version of record. This version will undergo additional copyediting, typesetting and review before it is published in its final form, but we are providing this version to give early visibility of the article. Please note that, during the production process, errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. © 2019 Published by Elsevier on behalf of the American Academy of Dermatology, Inc.
Part I: Retiform Purpura: A Diagnostic Approach Corey Georgesen, MD1; Lindy P. Fox, MD2; Joanna Harp, MD3 1. University of Pittsburgh Medical Center, Dept. of Dermatology 2. University of California, San Francisco, Dept. of Dermatology 3. Weill Cornell Medicine, Dept. of Dermatology
Correspondence: Corey Georgesen, MD UPMC Dermatology 9000 Brooktree Rd, Suite 200 Wexford, PA, 15090 Fax: 724-933-1338 [email protected]
Word and Figure Count: Part I: 2,819 words; 12 Figures, 1 Table All authors have approved the manuscript in its final form, and we have no conflicts of interest nor financial obligations to disclose.
Retiform purpura is a specific morphology within the spectrum of reticulate eruptions of vascular origin. This morpology develops when blood vessels serving the skin are compromised resulting in downstream cutaneous ischemia, purpura, and necrosis. Blood vessel compromise occurs by one of two mechanisms, 1) vessel wall damage (vasculitis/depositional disease/angioinvasion by organism) or 2) vessel lumen occlusion (thrombotic or embolic disease). Understanding the mechanisms that lead to retiform purpura helps inform the differential diagnosis.1-3
Recognition of retiform purpura is paramount, especially in the acute or severely ill patient, as it may elucidate the underlying diagnosis, provide prognostic information, and suggest a treatment approach. The differential diagnosis of retiform purpura is vast, reflecting the myriad conditions that can lead to cutaneous vessel wall damage or lumen occlusion. For example, a patient with bacterial sepsis may develop direct bacterial angioinvasion, reactive leukocytoclastic vasculitis, bacterial vaso-occlusive emboli, and/or disseminated intravascular coagulation, all of which can present with retiform purpura, although each through a distinct mechanism. Herein we describe an overview of the differential diagnosis of this cutaneous morphology, provide an approach to workup, and highlight updates in treatment of some of the more common conditions that manifest as retiform purpura.
2
We suggest the following clinical approach to the patient with retiform purpura: 1) What is the morphology of the lesion? 2) What is the status of the patient? 3) What is the location of the lesion? 4) What is the patient’s past medical and family history? 5) Are there any pertinent positives on review of systems? 6) Are there any additional relevant physical exam findings?
This six-step approach is designed to guide the clinician towards a narrowed differential diagnosis based on patient history and physical exam. However, it is important to note that most (if not all) patients with new onset retiform purpura warrant a skin biopsy and laboratory workup.
Step One. Morphology of the lesion. •
Retiform purpura refers to a distinct clinical morphology.
•
The differential diagnosis consists of pathophysiology centered on either the vessel lumen or the vessel wall.
First, what does retiform purpura mean from a morphologic perspective? These lesions present with a branching (reticular), non-blanching (purpuric) patch or plaque, which can occur anywhere on the body or mucous membranes.3 Lesions of retiform purpura are persistent and often accompanied by frank or impending central necrosis and/or ulceration. This contrasts with
3
other reticulate eruptions of vascular etiology including livedo reticularis and livedo racemosa. Livedo reticularis4 results from only partial or intermittent reduction of cutaneous blood flow leading to non-fixed, dusky patches forming complete rings reflecting the underlying cutaneous vasculature. (Figure 1A) Livedo racemosa, which is representative of a more irregular and significant reduction of blood flow, presents with broken rings that are persistent but rarely necrotic or ulcerative.5 (Figure 1B)
Unlike livedo, retiform purpura does not display the net-like pattern of rings, but instead displays branching at the periphery of a purpuric or necrotic center. Some authors have described it as “river-like” or “serpentine purpura,” and others note that the lesions may appear as “puzzle pieces” of livedo fit together.3 Lesions may be exquisitely painful reflecting the complete obstruction of blood flow to the skin with resultant ischemia and necrosis.2 We have provided representative lesions of retiform purpura (Figure 1A-D) to display the varied clinical presentation of these lesions. With experience and pattern recognition, these lesions are often immediately obvious.
Figures 2 summarizes the differential diagnosis of retiform purpura. When considering this vast differential, we find that it is helpful to first consider (and then confirm with skin biopsy) whether the disease pathology is within the vessel wall or the vessel lumen. If the disease centers on the vessel wall, the differential diagnosis includes depositional diseases (such as calciphylaxis6), angioinvasive organisms and vasculitides. While palpable purpura is the classic manifestation of small vessel vasculitis, concomitant retiform purpura indicates that a medium vessel component is also present. Thus, purely medium vessel vasculitides such as polyarteritis
4
nodosa7, in addition to small and medium mixed vessel vasculitides such as IgA vasculitis8 and cryoglobulinemia9, can occasionally present with retiform purpura, though this is not the most common presentation. On the other hand, if cutaneous histology reveals blockage of the vessel lumen, the differential diagnosis centers upon thromboembolic processes. Occlusion of cutaneous blood vessels can occur through a wide variety of mechanisms including hypercoaguable states (antiphospholipid syndrome10, disseminated intravascular coagulation, genetic disorders), platelet plugging (thrombotic thrombocytopenic purpura (TTP), hemolytic uremic syndrome (HUS), heparin induced thrombocytopenia (HIT)), elevated or dysfunctional red and white blood cells (polycythemia vera, sickle cell anemia, intravascular lymphoma), temperature-related processes (cryoglobulinemia11, cryofibrinogenemia), and finally embolic processes (septic, cholesterol, marantic). (Figure 23,5,12-14)
In an effort to narrow this wide differential diagnosis, some authors have recommended categorizing lesions as either “inflammatory” retiform purpura, or “non-inflammatory” retiform purpura.2-3 “Inflammatory” retiform purpura refers to the clinical presence of erythema around the lesion (accounting for a minimum of 2/3 of the lesion) with ≤ 1/3 of the lesion accounted for by central impending necrosis. “Inflammatory” retiform purpura suggests a vasculitic or infectious process. “Non-inflammatory” retiform purpura2-3 refers to clinical lesions presenting with 2/3 central frank or impending necrosis and ≤ 1/3 surrounding erythema and suggests an occlusive process. While this clinical categorization can be helpful in many cases, it is important to note that significant overlap exists. In addition, a few select diseases, i.e. cryoglobulinema, sepsis, and levamisole associated retiform purpura, may have both vasculitic and thrombotic pathophysiologic components. Therefore, while the degree of inflammation may be suggestive, a
5
strategized laboratory and pathologic evaluation (as detailed in subsequent sections of this manuscript) is necessary in all cases.
A final helpful clue when inspecting the morphology is the perceived acuity of the lesion. In a patient with multiple lesions of varying stages with atrophie blanche-like scarring of older lesions, one might surmise that skin lesions are resultant from a chronic, smoldering, intermittent process such as liveoid vasculopathy18. (Figure 3) In contrast, a patient with new onset of many lesions, all in a similar stage of development, may suggest a more acute, active process such as purpura fulminans (Figure 4) or a medication induced processes such as warfarin induced skin necrosis or hepatin induced thrombocytopenia.2,5,19 (Figure 5)
Step Two. Status of patient. •
Acute retiform purpura in a sick patient should prompt a search for serious and reversible causes.
•
It may be appropriate to send an initial battery of tests while awaiting skin biopsy results.
The next checkpoint is straightforward yet crucial. The clinician should briefly pause to consider the overall health of the patient. If, for example, the patient is severely ill, the clinician must first and foremost consider rapidly progressive, potentially fatal, and reversible causes. In many cases, this will mean proceeding with an initial battery of tests and urgent skin biopsy prior to moving any further in this diagnostic six-step algorithm.
6
In the emergent setting, when the patient presents with retiform purpura, fever, altered mental status, organ failure, and/or septic shock, we suggest a workup as outlined in Figure 620-30. Of course, workup should be discussed and followed with the intensivists, internists, and appropriate consultants. The dermatologist should pursue an immediate skin biopsy for hematoxylin and eosin (H&E) and tissue culture and direct immunofluorescence when appropriate. In the patient with systemic infection, tissue culture from the skin may identify the offending organism and provide antimicrobial sensitivity data. Broad-spectrum antibacterial and antifungal coverage should be initiated in septic or immunocompromised patients while awaiting results. The clinician should review the patient’s labs including platelet count and coagulation studies to evaluate for evidence of disseminated intravascular coagulation (DIC). Review of medications should be rapidly undertaken to identify if the patient is on any high-risk medications (newly started heparin or warfarin or drugs that can cause ANCA+ vasculitis) that may need to be held or changed while work up is underway.
Step Three. Lesion Location. •
Certain items on the differential diagnosis have characteristic anatomic locations.
•
Disseminated retiform purpura can encompass both infectious and non-infectious causes.
7
The anatomic distribution of retiform purpura can guide the clinician. (Figure 7) Some locations are classic, such as the free cartilage of the ear in levamisole-induced purpura31-32 (Figure 8) and peri-umbilical “thumbprint” purpura in disseminated strongyloides.33
Acral retiform purpura, especially on distal areas of the fingers and toes, should alert the clinician toward a possible embolic cause or cold-associated disease. Acral lesions (retiform purpura or a purpuric digit) accompanied by a recent cardiac procedure and an elevated eosinophil count suggest cholesterol emboli.34 (Figure 9) Patients with acral lesions and sepsis should be examined for cutaneous findings of endocarditis, including splinter hemorrhages, Janeway lesions (nontender, small petechiae on the palms and soles), and Osler nodes (painful erythematous papules), and an echocardiogram should be considered.35-36 In a patient with a history of systemic lupus, non-infective (marantic) endocarditis should be ruled out.37 Cryoglobulinemia (type I occlusive disease in the setting of myeloproliferative diseases and types II and III associated with cutaneous vasculitis) favors acral areas, including the ears and the nose, where body temperatures are lower.12
In lesions occurring predominantly on the lower extremities, vasculitides may be higher on the differential (especially if seen in conjunction with palpable purpura). If patients present with small punched out ulcerations and atrophie blanche (indicating chronicity) on the shins and dorsal feet, with a background of livedo, consider livedoid vascuopathy. In patients from Mexico and the Caribbean with lepromatous leprosy, an additional consideration would be the Lucio phenomenon.38-39
8
Purpuric lesions occurring on fatty areas of the abdomen and thighs might suggest warfarin or heparin induced skin necrosis. Warfarin induced skin necrosis classically starts within the first ten days of warfarin initiation (most often on days 3-5), when protein C levels hit nadir, and often occurs on the abdomen, thighs, buttocks, and breasts.5
Ecthyma gangrenosum40 and meningococcemia5,41 may present with acute disseminated lesions. In the setting of acute widespread purpura without an infectious source, catastrophic antiphospholipid syndrome, purpura fulminans, and calciphylaxis42 (uremic or non-uremic) should be considered.
Step Four. Medical and Family History. •
Next collect relevant medical and family history.
•
Use previous clues for guidance.
For all patients with retiform purpura, we suggest thinking through the following set of general medical and family history questions, which should be specifically tailored to the location and acuity of the lesions:
1) Does the patient have any relevant personal or family history? a. End stage renal disease is associated with calciphylaxis.9 b. Connective tissue disease can be associated with antiphospholipid syndrome. Additionally, small and medium vasculitis can be seen in the setting of Sjogren’s
9
syndrome and rheumatoid arthritis. Mixed cryoglobulinemia can be seen in the setting of rheumatoid arthritis and lupus.43 c. Previous history of cerebrovascular accident or spontaneous abortion may be indicative of the antiphospholipid syndrome.44 d. History of severe asthma or nasal polyposis as can be seen in eosinophilic granulomatosis with polyangitis.45-46 Ear, nose, and airway manifestations are also common presenting symptoms in polyangitis with granulomatosis.47 e. Hepatitis is associated with cryoglobulinemia type II and III5,43 and polyarteritis nodosa5. f. If history of malignancy, IgA (and/or leukemic vasculitis) should be considered.4855
g. History of hereditary hemoglobinopathies such as sickle cell disease, thalassemia, and spherocytosis must be asked. h. A family history of myeloproliferative disorders would highlight a tendency towards a hematologic disease that may present with cryoglobulinemia56. 2) Does the patient have any recent or active infections? a. Disseminated intravascular coagulation and purpura fulminans can occur in the setting of various infections, especially encapsulated Gram positive bacteria.2,5,57 b. Ecthyma gangrenosum is associated with Gram negative sepsis. c. Hemolytic uremic syndrome has been associated with Shiga-toxin producing E. Coli, pneumococcus, and influenza, among others.58 d. Cold agglutinins are associated with infections, most commonly Mycoplasma pneumoniae.59
10
e. Cutaneous polyarteritis nodosa is commonly associated with streptococcal infection.5,10 f. Streptococcal and upper respiratory viral infections are associated with IgA vasculitis (Henoch Schonlein purpura).60 g. Angioinvasive fungal infections typically present in severely immunocompromised patients with signs of infection but who are not responding to broad antibiotic coverage. 3) Has the patient started any new medications or had exposure to illicit drugs? a. Warfarin induced necrosis and heparin induced thrombocytopenia most often occur within the first 3-5 and 7-10 days of initiation, respectively5 b. Certain medications, most commonly tumor necrosis factor (TNF) inhibitors, propylthiouracil, hydralazine, minocycline, rituximab, and statins, among many others, have been implicated in drug induced vasculitis.61 c. Levamisole contaminated cocaine is associated with retiform purpura classically of the ears and acral areas.31-32 4) Has the patient undergone recent instrumentation? a. Embolization, most notably cholesterol emboli, are commonly associated with cardiac procedures.34
Step Five. Review of systems. •
Review of systems should be tailored toward the patient.
•
Cutaneous vasculitis necessitates a search for systemic involvement.
11
A comprehensive review of systems for the patient presenting with retiform purpura can be found in Table 12,3,5, 15-17, 19, 43, 62-67. However, it must be emphasized that the review of systems can (and should) be focused on entities highest on the differential diagnosis. For example, in the patient with retiform purpura and deep vein thrombosis, be sure to ask about pulmonary symptoms given concern for pulmonary embolism. In the patient from an endemic area, consider strongyloides and ask about malaise, fatigue, and pulmonary or gastrointestinal symptoms. In the patient with streptococcal infection, ask about abdominal pain, joint pain, and change in urine color.
Finally, whenever vasculitis is suspected, systemic involvement must be ruled out with the review of systems, in addition to the physical exam and laboratory workup. Systems affected by the various vasculidites include: neurologic (cerebrovascular accident, mononeuritis multiplex), ocular, head and neck (epistaxis, sinusitis), pulmonary (hemoptysis or chest pain), cardiac (chest pain), abdominal (pain, diarrhea, melena), musculoskeletal (arthralgia), and renal (change in urine color).2,7,17,43,63
Step Six. Associated Physical Exam Findings. •
Thorough physical examination is requisite in patients with retiform purpura.
•
Full skin examination is important as obscured areas can have diagnostic clues.
12
As outlined, previous steps in this diagnostic algorithm involve assessing lesion morphology, degree of inflammation, and location. A full physical examination is also essential to fully evaluate the patient who presents with retiform purpura. The heart and lung examination as performed by the intensivist should be reviewed for associated findings (the murmur of bacterial endocarditis, friction rub of pericarditis, rales of interstitial lung disease, etc.) A musculoskeletal exam should be performed. Muscles strength should be assessed with an emphasis on the pelvic and shoulder girdles. Careful palpation for lymphadenopathy should be performed.68-70
The final step in the diagnostic algorithm is a complete and thorough skin examination. A myriad cutaneous exam findings can give support to the suspected diagnosis.
Going (anatomically) from top to bottom, the physician should start in the scalp, looking for any sign of scarring alopecia as may be associated with connective tissue disease. The conchal bowls can be examined for signs of chronic cutaneous lupus. All mucous membranes should be inspected. Conjunctival hemorrhage can be suggestive of a platelet diathesis or disseminated intravascular coagulation.71 The nares deserve inspection, as nasal polyps and angioinvasive fungi (mucormycosis) can be obvious without endoscopy. The oral mucosa should be carefully examined for signs of ulceration, purpura, or xerostomia. Additionally, the clinician can look for the strawberry gingivitis of polyangitis with granulomatosis.72-75
The dermatologist should perform a full skin exam of the trunk, extremities, and genitals. The patient should be repositioned when necessary to observe obscured areas. No area should be neglected; areas under chest leads, adhesives, and surrounding I.V. sites must be examined, as
13
diagnostic lesions may otherwise remain concealed. (Figure 10) These are also potential sites of inoculation of invasive fungal organisms in the immunosuppressed hospitalized patient.
Finally, the nails deserve close inspection. Koilonychia, or spoon nails, can be observed in anemia that is associated with malignancy, autoimmune, or other chronic disease.76 Lindsay’s nails, or half and half nails, may be associated with chronic renal disease.77 Terry’s nails are associated with cirrhosis as can be seen in hepatitis C.78 Muehrcke’s nails, which present as parallel lines of blanchable leukonychia (pathology of the nail bed), are associated with low protein states such as nephrotic syndrome or liver disease.79 The proximal nailfold should be inspected for the presence of vascular dropout, meandering and dilated vessels, or frayed cuticles (Samitz sign80), which can signify the presence of autoimmune connective tissue disease.81-83 Finally, in the immunocompromised patient, nails should be inspected for inflammation and subungual discoloration, as fusarium and other angioinvasive organisms can disseminate from a primary cutaneous paronychia or onychomycosis.84-85
Completing the Workup •
Biopsy location should be selected to maximize probability of capturing representative pathology.
•
Laboratory evaluation will vary and is dependent upon previous steps detailed in the diagnostic algorithm.
14
Now the clinician is prepared to complete the diagnostic workup by performing a biopsy for H&E (plus tissue culture and/or direct immunofluorescence as deemed appropriate) and collecting laboratory data.
Biopsy should be collected at the peripheral purpuric rim of the lesion. When hemorrhagic bullae are present, as is often the case in bacterial and fungal sepsis, fluid can be obtained for bacterial culture and the blister roof should be scraped for potassium hydroxide examination. In other cases, biopsy specimens can be smeared on a glass slide for touch preparation, as described by other authors.86 Finally, in patients with suspected infection, consider obtaining a second biopsy from the necrotic center for tissue culture.87
The differential diagnosis of retiform purpura informs the laboratory evaluation. The extent and timing of laboratory work up will vary depending on the acuity of the skin manifestations, the overall health of the patient, and any relevant history and physical exam findings that may narrow the differential. If the patient is severely or acutely ill, it may be reasonable to send many tests immediately to try to narrow the differential while biopsy results are pending. If skin lesions are more chronic and/or stable, it may be preferable to await biopsy results, confirm if the pathology is in the vessel wall or lumen, and then work through the evaluation based on a narrowed differential diagnosis. Retiform purpura laboratory evaluation is detailed in Figure 113,5,15-17, 19,22,27,34,4363-64,88.
Prompt treatment should follow. Part II of this CME will detail these steps in relation to four of the most common causes of retiform purpura.
15
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29
Figure Legends.
Figure 1. (a) Livedo reticularis: Note the presence of complete rings. These are transient and often temperature related. (b) Livedo racemosa: Note the presence of broken, irregular, fixed rings.
Figure 2. Retiform purpura in a patient with (a) calciphylaxis, (b) septic vasculitis, (c) IgA vasculitis, and (d) disseminated intravascular coagulation
Figure 3. Differential diagnosis of retiform purpura based on pathophysiology.
Figure 4. Livedoid vasculopathy in a 39-year-old female with anti-phospholipid syndrome.
Figure 5. Pupura fulminans in presenting patients admitted to the intensive care unit.
Figure 6. Heparin induced thrombocytopenia-induced retiform purpura.
Figure 7. Workup for retiform purpura in the acutely ill patient.
Figure 8. Anatomic distribution of common causes of retiform purpura.
Figure 9. Levamisole-induced retiform purpura. (Photograph courtesy of Christine Ahn, MD).
30
Figure 10. Retiform purpura in the setting of cholesterol emboli following cardiac catheterization.
Figure 11. The “bullseye infarct” purpuric lesions of mucormycosis: A 6-year old with acute lymphoblastic leukemia presented with retiform purpura (a) next to an intravenous puncture site that evolved into a non-retiform purpuric plaque. A 52-year-old with in septic shock presents with a purpuric patch (c-d) under a chest lead. While not retiform in this photograph, systemic fungal infections can sometimes present with retiform lesions that quickly evolve into different morphologies.
Figure 12. Retiform purpura laboratory evaluation.
Table 1. Complete retiform purpura review of systems.
31
System
Symptom
General
fatigue weight changes
Associations
fever
connective tissue disease, leukemia/lymphoma, chronic infections (hepatitis, malaria, parasitic), endocarditis, anemia (sickle cell, paroxysmal nocturnal hemoglobinuria) malignancy, chronic infections connective tissue disease, leukemia/lymphoma, acute infection (bacterial, fungal), chronic infections (hepatitis, malaria, parasitic), endocarditis, ANCA vasculitis
conjunctival hemorrhage (red eye)
hemoglobinopathies, TTP, HUS, DIC, connective tissue disease
vision change
vasculitis (ANCA, leukemic, septic, cryoglobulinemia), infection (mucormycosis)
hearing change, tinnitus
vasculitis (ANCA, leukemic, septic, cryoglobulinemia)
Nose
epistaxis sinusitis
vasculitis (polyangitis with granulomatosis), thrombocytopenia (TTP, HUS, DIC) eosinophilic granulomatosis with polyangitis
Mouth
xerostomia recurrent ulcers
Sjogrens syndrome, connective tissue disease connective tissue disease
Neuro
headache
connective tissue disease (lupus), infection (meningococcemia, angioinvasive fungi), vasculitis, cryoglobulinemia
altered mental status numbness, loss of sensation loss of motor function seizure
infection (sepsis), TTP vasculitis (ANCA, polyarteritis nodosa), leprosy, cerebrovascular accident (antiphospholipid syndrome) vasculitis (ANCA, polyarteritis nodosa), leprosy, cerebrovascular accident (antiphospholipid syndrome) connective tissue disease (lupus)
Ocular
Ear
Respiratory
Cardiovascular
chest pain
connective tissue disease (pleuritis), hypercoagulative state (embolus)
shortness of breath hemoptysis
connective tissue disease (pulmonary hypertension, interstitial lung disease), hypercoagulative state (embolus), infection (endocarditis, pneumonia) infection (pneumonia), vasculitis (granulomatosis with polyangitis)
chest pain edema calf pain
connective tissue disease (carditis), cardiomyopathy (eosinophilic granulomatosis with polyangitis) renal disease (calciphylaxis), liver disease (cryoglobulinemia, IgA vasculitis),deep venous thrombosis (hypercoagulative state, antiphospholipid syndrome) deep venous thrombosis (hypercoagulative state, antiphospholipid syndrome)
appetite change
vasculitis (IgA, cryoglobulinemia, leukemic), bowel infarcation (hypercoagulable state, embolus, DIC), malignant atrophic papulosis vasculitis (IgA, cryoglobulinemia, leukemic) lymphoma (leukemic vasculitis, cryoglobulinemia, intravascular lymphoma), malignancy (IgA vasculitis), parasite (strongyloides)
jaundice/kernicterus
liver disease (cryoglobulinemia, IgA vasculitis)
Genitourinary
change in color dysuria
vasculitis (IgA, ANCA, cryoglobulinemia), connective tissue disease (lupus, systemic sclerosis), paroxysmal nocturnal hemoglobinuria infection (urosepsis)
Musculoskeletal
proximal weakness arthralgia
connective tissue disease (dermatomyositis) connective tissue disease (lupus, mixed connective tissue disease), cryoglobulinemia
Hematologic
ease of bruising
lymphoma (leukemic vasculitis, cryoglobulinemia, intravascular lymphoma), liver disease (cryoglobulinemia, IgA vasculitis), thrombocytopenia (TTP, HUS, DIC, HIT)
ease of bleeding
thrombocytopenia (TTP, HUS, DIC, HIT)
Gastrointestinal
pain melena