1 SUBMITTED 13 OCT 20 1 REVISIONS REQ. 9 DEC 20 & 8 FEB 21; REVISIONS RECD. 18 JAN & 21 FEB 21 2 ACCEPTED 23 FEB 20 3 ONLINE-FIRST: MAY 2022 4 DOI: https://doi.org/10.18295/squmj.5.2022.036 5 6 Loeffler's Syndrome and Multifocal Cutaneous Larva Migrans 7 Case report of an uncommon occurrence and review of the literature 8 *Abheek Sil,1 Dibyendu B. Bhanja,2 Atanu Chandra,3 Surajit K. Biswas1 9 10 1Department of Dermatology, Venereology, and Leprosy, RG Kar Medical College and 11 Hospital, Kolkata, India; 2Department of Dermatology, Venereology, and Leprosy; 12 Midnapore Medical College and Hospital, West Bengal, India; 3Department of Internal 13 Medicine, RG Kar Medical College and Hospital, Kolkata, India. 14 *Corresponding Author’s e-mail: abheek.sil@gmail.com 15 16 Abstract 17 Cutaneous larva migrans (CLM) is a zoonotic skin disease that is frequently diagnosed in 18 tropical and subtropical countries. Loeffler’s syndrome (LS) is a transient respiratory ailment 19 characterized by pulmonary infiltration along with peripheral eosinophilia and commonly 20 follows parasitic infestation. We report here an interesting case of a patient presenting with 21 LS that was attributed secondary to multifocal CLM. Treatment with seven-day course of oral 22 albendazole (400mg daily) coupled with nebulization (levosalbutamol and budesonide) led to 23 complete resolution of cutaneous lesions and respiratory complaints in two weeks. There was 24 complete resolution of pulmonary pathology at 4 weeks follow-up. As there are only a few 25 reported cases of LS associated with CLM, we also reviewed the literature on this rare 26 association. 27 Keywords: Loeffler's syndrome; peripheral eosinophilia; cutaneous larva migrans; multifocal; 28 disseminated; helminths, albendazole. 29 30 Introduction 31 Cutaneous larva migrans (CLM) is a distinct cutaneous entity that is relatively common in the 32 warmer tropical and sub-tropical regions. It is characterized by tortuous skin lesions attributed 33 2 to epidermal burrowing by certain helminthic larvae.1 Apart from the cutaneous affliction, this 34 condition is rarely uneventful. On rare occasions, CLM can culminate into Loeffler's syndrome 35 (LS), which is characterized by migratory pulmonary infiltrates and peripheral eosinophilia.2 36 Here we describe an interesting case of LS associated with multifocal cutaneous larva migrans 37 and review the literature on this uncommon association. 38 39 Case Report 40 An otherwise healthy 33-year-old gentleman presented with intense, non-productive cough for 41 the last 7 days with occasional breathlessness on exertion. The pulmonary symptoms were 42 accompanied by abrupt onset pruritic skin eruptions over chest and abdomen for the same 43 duration. Recently he had returned from a vacation to a nearby coastal town where he had spent 44 a significant time on the sandy beaches. There was no history of fever, hemoptysis, wheeze, 45 chest pain, allergic rhinitis or relevant drug intake (prescription, over the counter or illicit). His 46 primary care physician had initiated a 5-day course of oral azithromycin (500mg daily) without 47 any significant improvement. His medical and family history was non-contributory. On general 48 examination, he was afebrile, normotensive (126/78 mm Hg) with a saturation of 97% on room 49 air. Bi-basilar crackles was appreciated on chest auscultation. Cutaneous examination revealed 50 multiple discrete thread-like skin-coloured to erythematous serpiginous tract of various sizes 51 (4 to 12 cm in length) distributed over the chest and abdomen. (Figure 1) Focal excoriation 52 and pustules were noted over few lesions. Other mucocutaneous sites were uninvolved. 53 Evaluation of other organ systems was uneventful. 54 55 Laboratory examination was notable for peripheral eosinophilia (absolute eosinophil count 56 2200 cells/μL). Stool examination for ova, parasite, and cyst was negative. Chest radiography 57 showed ill-defined bilateral pulmonary infiltrates. A high-resolution computed tomography 58 (HRCT) thorax revealed the presence of ground-glass opacities mainly in mid and lower zone 59 of both lungs with predominant peripheral distribution. (Figure 2a) Based on suggestive 60 history, characteristic clinical presentation, laboratory and radiological findings, the final 61 diagnosis of Loeffler's syndrome secondary to multifocal cutaneous larva migrans was 62 established. He was treated with oral albendazole (400mg) once daily for 7 consecutive days 63 along with nebulization with levosalbutamol and budesonide as required. His respiratory 64 symptoms and cutaneous lesions completely subsided in 2 weeks. There was complete 65 radiological resolution at 4 weeks follow-up. (Figure 2b) 66 3 An informed written consent was obtained from the patient after full explanation regarding his 67 images being published for academic interest. The patient did not have any objection regarding 68 use of his images which may reveal his identity and gave due permission to use them. 69 70 Discussion 71 LS is a transient respiratory illness associated with peripheral eosinophilia as a response to 72 parasitic infestation or medications.3 Ascaris lumbricoides is most commonly implicated with 73 the condition followed by Trichuris, Strongyloides, Taenia saginata, Entamoeba histolytica, 74 and as a complication of chronic asthmatic states. However, it has rarely been reported with 75 CLM. In 1946, Wright and Gold first described 26 patients with cutaneous larva migrans who 76 developed Loeffler’s syndrome.4 Subsequently this rare complication of CLM has been 77 reported only in handful of cases.3, 5-16 Table 1 summarizes the previous published case report 78 of CLM with LS. 79 80 CLM, also termed as “creeping eruption,” is a parasitic infestation caused by the invasion and 81 migration of parasitic larvae in the skin. The burrowing of the larva of Ancylostoma braziliense, 82 Ancylostoma caninum, Necator americanus, Uncinaria stenocephala and Strongyloides 83 stenocephala have been implicated in such creeping eruptions.17 Adult hookworms infest the 84 intestines of cats and dogs and their ova in excreta hatch under favourable conditions. These 85 larvae then penetrate intact or abraded skin following exposure with soil contaminated with 86 faeces. Humans act as an accidental dead-end host as the travelling parasite perishes, and the 87 cutaneous manifestations usually resolve uneventfully within months. Warm, sandy, humid 88 and shady fields, sandpits or sea shores are particularly favoured areas. This makes barefoot 89 walkers, farmers, gardeners, hunters, hod carrier or beach visitors particularly susceptible to 90 acquire the infestation. Exposed anatomical sites like hands and feet are usually affected. 91 However, involvement of atypical locations like the buttocks, genitalia, scalp, and multifocal 92 or disseminated lesions have also been rarely reported in the literature. Clinically an initial 93 small reddish papule progresses to a serpiginous pruritic rash with a slow rate of progression 94 from less than 1–2 cm/day.1, 17-20 CLM may be complicated by secondary bacterial infection, 95 allergic reaction, eczematisation, or very rarely LS. Concurrently or subsequently patient may 96 develop non-productive cough, exertional breathlessness, exacerbation of pre-existing asthma 97 which should raise the clinical suspicion of LS. Interestingly, a unique case of asymptomatic 98 LS in CLM has been reported recently.12 99 4 The exact pathogenesis of pulmonary infiltrates in CLM remains poorly understood. The 100 current understanding encompasses a systemic immunologic process in which hookworm in 101 the skin leads to generalized sensitization. The lung reacts with the soluble larval antigen and 102 produces the eosinophilic pulmonary infiltration. The complete resolution of pulmonary 103 infiltrates and skin eruptions with oral anti-helminths supports this proposed mechanism.21 104 Associated eosinophilia is teleologically related to the role of eosinophils in parasitic 105 destruction. In parasitic infestation like CLM, eosinophilic chemotaxis may result from IgE-106 mediated reactivity against the infestant, direct chemotactic property of certain parasites, T-107 cell dependent mechanism, and immune-complex related.13 108 109 The differential diagnoses we considered for the cutaneous lesions included larva currens, 110 migratory myasis, gnathostomiasis, cercarial dermatitis, allergic contact dermatitis, 111 inflammatory tinea, and scabies. All the above mentioned conditions were ruled out based on 112 history, and clinical examination. Loeffler’s syndrome should be considered early in the 113 differential diagnosis for community acquired pneumonia and asthma unresponsive to classic 114 antibiotic therapy in individuals with associated cutaneous pruritic eruption. Pulmonary 115 fibrosis and respiratory failure may rarely complicate LS.3, 6, 7, 22 116 117 The condition is primarily self-limiting but appropriate pharmacological intervention leads to 118 faster resolution. Veraldi et al23 reported a new therapeutic regimen of oral albendazole 119 (400/day for 7 days) to be highly effective. Single dose therapy of oral ivermectin (200ug/kg) 120 is equally effective with near 100% cure rates. Topical 10% thiabendazole may be used as an 121 alternative. Opting for surgery or cryotherapy rarely proves to be effective. Sometimes 122 supportive therapy like oxygen inhalation, systemic, or inhalational corticosteroids may be 123 required to alleviate the respiratory symptoms.4, 8, 9, 24 124 125 Conclusion 126 In conclusion, we report this case to add to the existing literature on this rare association. LS 127 secondary to multifocal CLM has rarely been documented previously. LS should be considered 128 early in the differential diagnosis for respiratory complaints in association with pruritic 129 cutaneous eruption especially in an individual having recently returned from a vacation at a 130 tropical destination. In this era of global migration, physicians should be aware of the 131 uncommon systemic manifestation of this uncommon tropical infestation and provide prompt 132 treatment to avoid long-term complication. 133 5 Authors’ Contribution 134 AS, DBB and AC drafted the manuscript. AS and SKB contributed to patient management, 135 review of literature and critical revision of the manuscript. All authors approved the final 136 version of the manuscript. 137 138 References 139 1. Brenner MA, Patel MB. Cutaneous larva migrans: the creeping eruption. Cutis 140 2003;72:111-5. 141 2. Ekin S, Sertogullarindan B, Gunbatar H, Arisoy A, Yildiz H. Loeffler's syndrome: an 142 interesting case report. Clin Respir J 2016;10:112-4. 143 3. Podder I, Chandra S, Gharami RC. Loeffler's syndrome following cutaneous larva 144 migrans: An uncommon sequel. Indian J Dermatol 2016;61:190-2. 145 4. Wright DO, Gold EM. Loeffler's syndrome associated with creeping eruption 146 (cutaneous helminthiasis). Arch Int Med 1946;78:303. 147 5. TeBooij M, de Jong E, Bovenschen HJ. Löffler syndrome caused by extensive 148 cutaneous larva migrans: a case report and review of the literature. Dermatol Online J 149 2010; 16:2. 150 6. Del Giudice P, Desalvador F, Bernard E et al. Loeffler's syndrome and cutaneous larva 151 migrans: a rare association. Br J Dermatol 2002;147:386-8. 152 7. Tan SK, Liu TT. 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Clin Infect Dis 2000;30:811–4. 190 7 Table 1: Comparison of clinical characteristics of previous case reports of Loeffler’s syndrome 191 in association with cutaneous larva migrans 192 Case report (year) Country Age, sex Travel / Exposure history Location of CLM Pulmonary symptoms Absolute eosinophil count(mm3) Imaging finding (chest X-ray and/or CT scan) Treatment Outcome Guill MA et al (1978) USA 40,M and his spouse 36,F Vacation in Gulf of Mexico Feet Non- productive cough, tightness in chest, exertional dyspnoea 7598 (male) and 2528 (female)* Multiple patchy consolidations in lung fields (CXR) Thiabendazole oral suspension, 0.1% triamcinolone acetonide cream (four times daily), symptomatic management for respiratory symptoms Resolution after 8 weeks of onset of symptoms Butland RJ et al (1985) UK 58,F Holiday trip to Barbados Buttocks, legs and abdomen Cough 3000 Ill-defined patchy shadowing in the left upper and middle zones (CXR) Topical thiabendazole Complete resolution within 2 months Wong- Waldamez A et al (1995) Guatemala 21,M None Disseminated bullous lesions over trunk and extremities (especially lower) None 710 Diffuse miliary infiltrate in both lung fields (CXR) Single dose albendazole (400 mg) Resolution in one week Del Giudice P et al (2002) France 41,M Holiday trip to Thailand Left foot Intense non- productive cough 1100 Ill-defined reticulonodular infiltrates in both lungs (CT scan) Oral thiabendazole (25 mg/kg) twice daily for 10 days; oral corticosteroids 1 mg/kg daily Complete resolution within 5 days Schaub N et al (2002) Switzerlan d 39, M Holiday trip to Thailand On the buttocks Dyspnoea 1616 Bilateral diffuse ground-glass opacities (CXR; further confirmed on CT scan) Oral albendazole 400 mg on 5 consecutive days and a single dose of oral praziquantel (3600 mg) Complete resolution TeBooij M et al(2010) Netherland s 27, M Holiday trip to Thailand Both feet Exacerbation of pre-existing asthma 2700 Small nodular granular infiltrates and linear paracardial opacities in both lungs (CXR) Ivermectin, inhalation medication (budesonide/formoterol) andtopical potent steroid Complete resolution Tan SK et al (2010) Singapore 47,M Trip to beach holiday in Bali, Indonesia Both feet and his right thigh and buttock Dyspnea, wheezing and chest discomfort 2903 Reticulonodular infiltrates in the right middle and lingular lobes (CXR and CT scan) Oral mebendazole (3 days) followed by Albendazole and intravenous hydrocortisone (5 days) with oxygen supplementation Complete remission in 2 weeks Darocha S et al (2011) Poland 28,M Trip to Sri Lanka Both feet Cough and dyspnoea at rest with exacerbation of asthma 3400 Multiple poorly defined consolidations and ground-glass attenuation areas, some of them peripherally involving bilateral upper and lower lobes (CT scan) Salbutamol, nebulisation with budesonide, prednisolone, topical albendazole Complete resolution on scheduled follow-up after 3 months Podder I et al(2016) India 30,M Agriculturi st Both hands Non- productive cough 5200 Fleeting opacities (CXR) Oral albendazole (400 mg/day) for 5 days Complete resolution 8 *The maximum absolute eosinophil count recorded during hospital stay 193 Abbreviations: M=male, F=female, CXR=chest X-ray, CT=computed tomography scan 194 occasional exertional breathlessness Wang S et al (2017) China 6,M Vacation in Malaysia Left pretibial and tarsal skin eruptions Severe cough 1870 Bilateral small nodular infiltrates in lower lungs (CXR) Oral albendazole (400mg/day) for 7 days Complete resolution in 2 weeks Gao YL et al (2019) China 26, F A trip to Sabah, Malaysia Right upper and lower extremity Non- productive cough and occasional breathlessness Mild eosinophilia Showed ill-defined reticulonodular infiltrates in both lungs (CT scan) Oral albendazole 400 mg for seven consecutive days Complete resolution within 7 days Ng J et al (2021) USA 52, M Working outside - barefoot in an area where feral cats frequently defecate Right foot, chest and abdomen Asymptomatic 2100 Nodular opacities bilaterally (CXR) Oral albendazole 400 mg single dose Complete resolution Present case (2021) India 33, M Farmer Chest and abdomen Intense, non- productive cough with occasional exertional breathlessness 2200 Ill-defined pulmonary infiltrates (CXR); nodular opacities bilaterally (CT scan) Oral albendazole (400mg) once daily for 7 consecutive days along with nebulization with levosalbutamol and budesonide Respiratory and cutaneous lesions resolved within 7 days; complete radiological resolution on 4 weeks follow-up 9 195 Figure 1: Multiple discrete thread-like skin coloured to erythematous serpiginous tract of 196 various sizes (4 to 12 cm in length) distributed over the abdomen (a) and chest (b) 197 198 199 Figure 2: (a) Computed tomography of chest showed the presence of ill-defined 200 reticulonodular infiltrates in both lungs; (b) Complete resolution after 4 weeks 201