Case 5 Leg Edema 26 year-old woman presents to a clinic in rural Malawi with chief complaint of bilateral lower extremity

edema. She noted persistent bipedal swelling one year ago when pregnant with her fourth child, and is now worried about a few ugly bumps which appeared several months ago on both feet. She complains of tightness and mild pain in her legs and thighs, especially with long walks. The swelling does not improve when recumbent. There is no history of leg ulcers. She has had no fever, night sweats, shortness of breath, dyspnea on exertion, orthopnea, cough, jaundice, abdominal pain, dysuria, hematuria, nausea, vomiting, weight loss, melena or hematochezia. Her urine has been clear, and she also denies any prolonged febrile illnesses before and since her edema started. Her prior pregnancies were not associated with edema, and her last pregnancy and delivery were normal. Of note, aside from a child who died recently after developing edema all over his body, she does not recall anyone in her village having similar swelling in their legs. She lives in a relatively flat region, with no hills and no rivers/lakes. Her HIV status is unknown. There is no personal history of TB, and no known TB contacts. She has never smoked and does not drink alcohol. Her husband died 4 months ago from a diarrheal illness, but had been chronically ill with weight loss and weakness for some time before that. Physical Exam: T: 37.3 C HR: 72, BP 110/65, RR: 14, Wt: 47.5 kg, Ht: 1.55m General: No acute distress, thin appearing, but not wasted HEENT: Pupils equally reactive to light, extraocular movements intact, conjunctiva slighty pale. No icterus, cervical lymphadenopathy, thrush or oral lesions. CHEST: Lungs clear bilaterally. Heart sounds regular without murmurs, rubs or gallops. Normal PMI. No JVP visible above sternum at 20 degrees elevation. ABDOMEN: Soft, without tenderness, distention, or shifting dullness. Liver is 2 cm below costal margin, spleen tip barely palpable, no CVA tenderness NEURO: No focal abnormalities are found EXTREMITIES: Normal upper extremities. Lower extremities grossly edematous, non-pitting, non-tender, firm/woody to touch in both feet and up to midshin bilaterally. +Bilateral inguinal lymphadenopathy, with ~10cm area of firm, hyperpigmented, edematous skin in groin SKIN: ~0.5 to 1cm verrucous growths on both feet (totaling 8 lesions), nonumbilicated, non-ulcerated, non-tender. On upper right upper thigh ~15 hyperpigmented, firm, nodular lesions ~1-1.5cm in diameter noted, nontender, non-pruritic. (See pictures)

Figure 1. Right foot.

Figure 2. Right thigh.

1. What is the frame of this case (i.e. the key clinical features the final diagnosis has to be consistent with or explain)? -- 26 year old woman in rural Malawi -- husbands recent death from chronic illness -- bilateral lower extremity swelling, non-pitting, -- swelling is progressive over 1 year, and appeared before skin lesions appeared -- no shortness of breath or cough, JVP flat, no crackles or ascites -- verrucous lesions on feet with hyperpigmented nodules bilaterally, -- non-tender lymphadenopathy with 10 cm of firm edema in groin 2. What is your differential diagnosis? What elements of the history and physical support or reject your diagnoses? Differential Diagnosis: Kaposi Sarcoma, filarial elephantiasis, fungal infection (e.g. chromoblastomycosis), podoconiosis, chronic renal failure, congestive heart disease, chronic liver failure, chronic venous stasis. Filarial disease is found extensively in sub-Saharan African countries, and often results in woody edema of the lower extremities. However, edema generally progresses very slowly, over the course of years, so it would be unusual for this patient to develop such extensive edema in just one year unless the history is (very) inaccurate. Also, filarial edema usually presents unilaterally, and this patient has bilateral disease. The absence of similar symptoms among other people in patients village also points away from filarial disease, as it tends to occur in clusters. Fungal infections can also present with this clinical picture, with cauliflower like coalesced growths, firm, non-pitting edema, and satellite lesions. These advanced infections are usually seen in tropical and subtropical regions, mostly affecting the rural population. This infection, called chromoblastomycosis, can be caused by a number of fungal species, most commonly Fonsecaea pedrosoi, Phialophora verrucosa, and Cladosporium Carrionii. However, fungal infection is also usually a process that takes years to become this advanced, so our suspicion in this patient is less. Another aspect that points less to fungal infection is the existence of non-pitting edema prior to any skin findings - which suggests a primary lymphatic/vascular process rather than a primary skin process. Podoconiosis, or non-filarial elephantiasis, is a chronic condition caused by exposure of bare feet to inorganic elements in certain types of soil that over the course of years can lead to lymphatic fibrosis and asymmetric edema of the lower extremities. This disease is most prevalent in equatorial regions of Africa and especially in areas with hills. This condition is uncommon epidemiologically in Malawi.

Chronic renal failure, heart failure, liver failure, and chronic venous stasis all can present with woody edema. For this patient, her story has no hallmarks of renal failure (normal urine, blood pressure is normal), heart failure (no SOB, no rales on lung exam, no elevated JVP, no cardiac murmur, normal heart rate), nor liver failure (no ascites, no jaundice, no abdominal pain, non-pitting edema instead of pitting). Chronic venous stasis is also less likely given the time course (usually over many years), non-pitting nature of patients edema, and lack of ulcers. Kaposi Sarcoma (KS) is a neoplastic process of endothelial cells and is associated with HHV-8 (Human Herpes Virus-8) infection, and has been described mostly in people with immunosuppression, especially among HIV patients. KS is one of the most common tumors in HIV positive patients in Sub-Saharan Africa, and is the most common cause of unilateral lower extremity edema in Malawi. These tumors are highly vascular and can grow rapidly. The risk for KS is highest in those with lower CD4 counts, but can occur at any CD4 level. Most commonly, the disease presents with dark, nodular skin lesions, matted lymphadenopathy (often in the inguinal region), and woody, non-pitting edema of the areas involved. KS lesions can be found anywhere in the body, including the lungs (often producing hemoptysis and mimicking TB), and gut (causing melena). While most cases of KS currently occur in HIV infected individuals, there is a slowly progressive form of KS that predates the HIV pandemic, that is not associated with HIV infection or immunosuppression, and that is endemic in the so called Kaposi Sarcoma Belt in equatorial Africa. In this patient, KS should be one of the top diagnoses on our differential given the physical findings, the epidemiologic background, and the circumstances of her husbands death (very suspicious for AIDS). If patients HIV status is positive, then the likelihood of KS increases even further.

3. What testing is indicated at this point? Commonly available tests: Urine dip analysis Specific Gravity: 1.015, nitrite negative, no WBCs, no RBCs, no protein, no casts, no glucose, no ketones. HIV rapid test positive Creatinine 1.2 mg/dl 4. How do these tests narrow your differential diagnosis? We can likely rule out chronic renal failure as the creatinine is normal and the urine dip shows no protein. The HIV seropositivity should greatly increase our suspicion for KS, and should prompt us to further characterize the circumstances of the patients husbands death as he likely died of an AIDS-related illness (consider discussing the use of the verbal autopsy to establish husbands likely diagnosis). We should also attempt to obtain a more detailed history and exam to give the patient a WHO clinical stage (e.g. 4

weight loss, recent infections such as abscesses, pneumonia, zoster, etc.). A clinical diagnosis of KS would have the patient at WHO clinical stage 4 AIDS. It would be important to document any potential visceral involvement of KS, including detailed exam of the conjunctiva, oral mucosa, and a fecal occult blood test. At this point, while much lower on the differential diagnosis (likely < 5% pre-test probability), we still cannot rule out filarial disease, podoconiosis (though less likely from epidemiologic standpoint), or fungal process. 5. What should be your initial management approach be for this patient? Are there other tests that can be useful? A urine pregnancy test should be done as PCP prophylaxis is indicated for this patient at this time. In many resource-poor settings, CD4 counts are not readily available or are cost-prohibitive, in which case a clinical diagnosis of KS would prompt us to initiate HAART as soon possible, as KS is a WHO clinical stage 4 diagnosis. The choice of initial therapy will depend on the patients pregnancy status. In most areas, histopathological diagnosis will not be available to confirm a diagnosis of KS, but where possible, a punch biopsy should be performed to diagnosis KS and rule out a fungal process. Other testing: Urine pregnancy (HCG) test negative Blood film (midnight) for filariasis no filarial forms seen CD4 120 cells/mm3 Guaiac positive Skin scraping microscopy after KOH exposure no fungal forms seen Punch biopsy of thigh lesion no parasites seen, no hyphae, yeast or other fungal forms seen, hypervascular invasion consistent with Kaposi Sarcoma. 6. Any other steps you would take at this point? It would be extremely important to arrange for the patients children to be tested. We should also encourage the patients current and past sexual partners to be tested. We should also want to know if the patient is breastfeeding her infant, and if so, to determine the babys (depending on age) serologic status using DNA PCR or rapid testing. If the child is HIV-negative, and there are resources available, the mother should be offered formula and a source of clean water. If the child is seropositive, then the mother should continue to breastfeed.

The patient should also have a thorough evaluation to rule out co-infection with sexually transmitted illnesses (STI), and TB. 7. What are the long-term treatment options for this patients condition? The recommended initial therapy in HIV-positive patients with a new diagnosis of KS is initiation immediately of HAART. Often, with HAART alone, KS lesions may improve or stabilize. Of note, patients can present shortly (within days to weeks) after HAART with worsening KS signs and symptoms that could be consistent with KS immune reconstitution (KS-IRIS). Depending on the severity of the IRIS, treatment with corticosteroids may be necessary. For KS lesions in isolation, cryotherapy, surgical excision, radiation, or intralesional chemotherapy have been used, primarily in resource-rich settings. For more extensive KS that has not responded despite HAART, systemic chemotherapeutics have been found to be useful (where available). A number of systemic chemotherapies are in use in resource-rich areas including liposomal doxorubicin and paclitaxel. In resource-poor regions, often only vincristine and bleomycin are available. Use of chemotherapeutic agents should not be attempted without adequate laboratory abilities (minimum LFTs, complete blood counts, basic chemistries). Familiarity with pre-hydration techniques and the management of adverse reactions (e.g. anaphylaxis, fever and neutropenia) is also crucial before starting chemotherapeutic agents. Thus, because of the level of resources needed to treat advanced KS, the patient may need to be transferred to a regional or tertiary health care center if possible. Further reading: Szajerka, T., Jabecki, J. Kaposis sarcoma revisited. AIDS Reviews 2007;9:230-6 Vanni T, Sprinz E, Machado MW, Santana Rde C, Fonseca BA, Schwartsmann G. Systemic treatment of AIDS-related Kaposi sarcoma: current status and perspectives. Cancer Treatment Reviews. 2006 Oct;32(6):445-55.

Phuoc V. Le, MD, MPH, Jonathan Crocker, MD Partners in Health -- Malawi