The Brief Case: Cases from 3 hospitals in Puerto Rico

Pulmonary alveolar proteinosis, idiopathic hypereosinophilic syndrome, and more.


Case 1: Pulmonary alveolar proteinosis

Cristina Martinez-Recio, MD, and William Rodriguez-Cintron, MD, MACP

The patient

A 66-year-old man with a history of hypertension, diabetes mellitus, and chronic kidney disease presented with a chief symptom of dyspnea on exertion of 6 months' duration. There was no history of tobacco use, weight loss, chest pain, fever, chills, cough, sputum, hemoptysis, or night sweats.

Crazy paving pattern Image courtesy of Dr William Rodriguez-Cintron
“Crazy paving pattern.” Image courtesy of Dr. William Rodriguez-Cintron.

Upon presentation, physical examination was unremarkable except for scattered bilateral inspiratory crackles on lung auscultation; oxygen saturation on room air was 94%. There was no peripheral cyanosis, clubbing, or edema. Laboratory findings were normal except for chronic elevation of creatinine and urea levels (2.01 mg/dL, and 34.2 mg/dL, respectively). HIV antibodies were negative, and the following levels were all within normal limits: lactate dehydrogenase, inflammatory and rheumatologic markers, and immunoglobulins. Tuberculin skin test was negative. Pulmonary function testing was normal with mild reduction in diffusing capacity for carbon monoxide (62% predicted). Arterial blood gas on room air revealed borderline hypoxemia (PaO2 70 mm Hg) and a widened alveolar-arterial gradient of 38 mm Hg (Figure 1).

Crazy paving pattern Image courtesy of Dr William Rodriguez-Cintron
“Crazy paving pattern.” Image courtesy of Dr. William Rodriguez-Cintron.

A non-contrast CT of the chest revealed patchy areas of parenchymal density without obscuration of the vascular markings and thickening of interlobular septa, producing the so-called “crazy paving pattern” (Figures 1 and 2). Bronchoscopy was performed, and bronchoalveolar lavage (BAL) fluid was opaque and milky in appearance. BAL periodic acid-Schiff (PAS) staining was positive for eosinophilic lipoproteinaceous material; acid-fast bacilli, fungal, and bacterial smears and cultures showed no findings or growth. The patient ultimately declined further therapeutic measures and is receiving ongoing outpatient follow-up in the pulmonary clinic (Figure 2).

The diagnosis

This patient has pulmonary alveolar proteinosis (PAP). PAP is a rare clinical syndrome that was first described in 1958. Subsequently, over 240 case reports and small series have described at least 410 cases in the literature. It is characterized by the alveolar accumulation of surfactant components with minimal interstitial inflammation or fibrosis. The median age at diagnosis is 39 years for men and 35 for women. Patients are usually smokers, with a median duration of symptoms before diagnosis of 7 months. Open lung biopsy, previously the gold standard for diagnosis, has decreased in frequency. Currently, the diagnosis of PAP can be established in 75% of suspected cases by the classic finding of a milky effluent from BAL. In addition, findings on high-resolution CT scan of the “crazy paving pattern” are highly sensitive for PAP.

PAP has a variable clinical course, ranging from spontaneous resolution to death. Deletion of genes for the granulocyte-macrophage colony-stimulating factor (GM-CSF) or the GM-CSF receptor are currently postulated as playing an integral role in disease pathogenesis, and GM-CSF replacement therapy has shown promise in patients with acquired disease. The most effective proven treatment—whole lung lavage—was described soon after the first recognition of the disease. However, this is reserved for only the most symptomatic patients with severe defects in diffusion capacity.

Pearls

  • PAP should be considered in the differential diagnosis in patients with dyspnea, hypoxia, and diffuse lung infiltrates, especially with the characteristic “crazy paving pattern.”
  • Whole lung lavage and GM-CSF replacement are potential therapies for PAP, but many patients are followed symptomatically without treatment.

Case 2: Strongyloides hyperinfection

Sandra Galarza-Vargas, MD, and William Rodriguez-Cintron, MD, MACP

The patient

A 63-year-old man presented to the hospital due to gastrointestinal symptoms secondary to ileal obstruction. Significant wall thickening of the proximal jejunum was noted on abdominal CT scan, and biopsy demonstrated the presence of a parasitic infection. Treatment with oral ivermectin led to clinical improvement. Three months later, the patient returned to the hospital with an anterior mediastinal mass, proven to be a thymoma. Together with the findings of hypogammaglobulinemia, the diagnosis of Good's syndrome was established. Four courses of chemotherapy were administered for the thymoma.

The patient presented again 7 months later with intractable vomiting and abdominal and chest pain. Physical examination revealed an oral temperature of 36.7°C (98.1°F) with normal blood pressure, sinus tachycardia, and dry oral mucosa. His abdomen was mildly tender to palpation, with present peristalsis. Respiratory and cardiac examinations were unremarkable. No neurological deficit was noted. There was no electrocardiographic or serum enzyme evidence of myocardial ischemia. Repeat abdominal CT imaging showed inflammation and focal dilatation of proximal jejunum.

Periumbilical urticarial rash Image courtesy of Dr William Rodriguez-Cintron
Periumbilical urticarial rash. Image courtesy of Dr. William Rodriguez-Cintron.
New diffuse alveolar and ground glass opacities on CT scan of chest Image courtesy of Dr William Rodriguez-Cintron
New, diffuse, alveolar, and ground glass opacities on CT scan of chest. Image courtesy of Dr. William Rodriguez-Cintron.
Bronchioalveolar lavage findings consistent with diffuse alveolar hemorrhage Image courtesy of Dr William Rodriguez-Cintron
Bronchioalveolar lavage findings consistent with diffuse alveolar hemorrhage. Image courtesy of Dr. William Rodriguez-Cintron.
Parasitic organisms morphologically consistent with Strongyloides stercoralis from BAL cytopathology report Image courtesy of Dr William Rodriguez-Cintron
Parasitic organisms morphologically consistent with Strongyloides stercoralis, from BAL cytopathology report. Image courtesy of Dr. William Rodriguez-Cintron.

The patient's condition deteriorated, with gram-negative bacteremia, sepsis, and hypoxemic respiratory failure leading to mechanical ventilation. His abdomen became increasingly distended and he developed a periumbilical urticarial rash (Figure 3). New, diffuse, alveolar, and ground glass opacities were seen on CT scan of the chest (Figure 4). Bronchioalveolar lavage (BAL) demonstrated findings consistent with diffuse alveolar hemorrhage (Figure 5). BAL cytopathology reported parasitic organisms morphologically consistent with Strongyloides stercoralis (Figure 6).

The patient was initially treated with oral ivermectin, although after 7 days there was no clinical improvement and persistent parasites were demonstrated on repeat BAL analysis. Rectal ivermectin and oral albendazole were added to oral ivermectin. After 3 weeks, the patient still showed presence of motile parasites on wet mounts of BAL. Subcutaneous ivermectin in combination with albendazole was then used in conjunction with immunoglobulin replacement therapy, and ultimately parasite clearance was achieved. A total of 8 consecutive weeks of anthelmintic therapy was needed to eradicate the parasite on BAL samples.

The diagnosis

This patient's diagnosis is Strongyloides stercoralis hyperinfection and associated diffuse alveolar hemorrhage (DAH). Strongyloides stercoralis affects 30 to 100 million people worldwide and is a common cause of abdominal pain and diarrhea. This nematode is predominantly found in tropical and subtropical areas, including Puerto Rico and the southeastern U.S. Strongyloides infection can be clinically categorized into 3 types: acute, uncomplicated chronic, and complicated chronic (also called disseminated or hyperinfection syndrome). Glucocorticoid treatment and human T-lymphotropic virus type 1 infection are the 2 conditions most specifically associated with triggering hyperinfection; however, cases have been reported in association with hematologic malignancy, malnutrition, and AIDS.

Periumbilical urticarial rash Image courtesy of Dr William Rodriguez-Cintron
Periumbilical urticarial rash. Image courtesy of Dr. William Rodriguez-Cintron.

Clinical presentation of hyperinfection may include nausea, vomiting, diarrhea, weight loss, cough, fever, or dyspnea. Gram-negative bacteremia due to gut translocation often occurs. Dermatologic manifestations, including urticaria and larva currens rash (as shown in Figure 3) may be present. Complications such as intestinal obstruction, ileus, hemodynamic instability, and significant gastrointestinal bleeding may occur. Very few cases of synchronous DAH and Strongyloides infection have been documented in the literature. This patient's history of parasitic infection, immunodeficiency, and chemotherapy all heightened his risk for this complicated parasitic infection.

Pearls

  • Strongyloides stercoralis is common and frequently undiagnosed, as many cases are asymptomatic; however, infection may be severe and even life-threatening in susceptible hosts.
  • Early diagnosis and eradication of Strongyloides stercoralis before initiation of immunosuppressive therapy can be life-saving. A high index of suspicion is required, especially in endemic areas.

Case 3: Histoplasmosis capsulatum: a rare presentation in an immunocompromised host

Pedro A. Torrellas Ruiz, MD; Juan C. Malpica Santiago, MD; Ronald Vigo, MD, ACP Member; Hiram Maldonado, MD, ACP Resident/Fellow Member; and Ricardo Fernandez Gonzalez, MD, FACP

The patient

A 34-year-old man with a history of HIV infection presented to the ED reporting fatigue, fever, chills, abdominal pain, and dry cough for 3 days. He had not had any previous opportunistic infections and was not taking antiretroviral therapy. He lived in a wooden house with poor roofing and pigeons in close proximity. Physical examination revealed a cachectic man with tachypnea, tachycardia, and orthostatic hypotension. Pulmonary examination was remarkable for inspiratory and expiratory crackles in the mid-lung fields and dullness to percussion at the right lung base. Hepatomegaly, involuntary guarding, and tenderness to palpation in the right and left upper abdominal quadrants were evident. No lymphadenopathy or skin lesions were noted.

Right-sided pleural effusion on chest X-ray Image courtesy of Dr William Rodriguez-Cintron
Right-sided pleural effusion on chest X-ray. Image courtesy of Dr. William Rodriguez-Cintron.
Cytologic analysis shows Histoplasma capsulatum using periodic acid-Schiff and Grocott stains Image courtesy of Dr William Rodriguez-Cintron
Cytologic analysis shows Histoplasma capsulatum using periodic acid-Schiff and Grocott stains. Image courtesy of Dr. William Rodriguez-Cintron.

Laboratory examination revealed anemia with thrombocytosis but no electrolyte disturbances. Liver tests were normal except for isolated elevation in alkaline phosphatase. Abdominal CT scan revealed hepatomegaly and retroperitoneal and mesenteric lymphadenopathy. Chest X-ray revealed a right-sided pleural effusion (Figure 7). A diagnostic and therapeutic thoracentesis revealed yellow, cloudy, pleural fluid. Fluid analysis revealed an exudate with pH of 7.5, a white blood cell count (WBC) of 802 cells/µL, and abundant neutrophils. Cytologic analysis revealed Histoplasma capsulatum using periodic acid-Schiff and Grocott stains (Figure 8). The patient's CD4 cell count was found to be 29 cells/µL, consistent with a diagnosis of AIDS.

The diagnosis

This patient with newly diagnosed AIDS has pulmonary histoplasmosis. Histoplasmosis has been reported worldwide, but the most common areas include North, Central, and South America as well as parts of Europe and Africa. Histoplasmosis infection has been diagnosed in 2% to 5% of the HIV-positive population. In immunosuppressed patients or those with deficient cell-mediated immunity, pulmonary infection via conidia inoculums frequently progresses to involve multiple lobes. In patients with AIDS, histoplasmosis presents as a progressive disseminated infection in 95% of cases. Most AIDS patients with disseminated disease have CD4 counts below 150 cells/µL, with a median of 50 cells/µL. Patients with disseminated disease usually present with fever, weight loss, and malaise over a period of several weeks. In about half of cases, vague respiratory symptoms are reported.

In patients with severely suppressed immune systems, histoplasmosis rarely causes focal infiltrates; rather, a diffuse interstitial or reticulonodular pattern most often occurs. The radiographic pattern often resembles those of Pneumocystis jiroveci (formerly carinii) pneumonia (PCP) or miliary tuberculosis, and patients can be co-infected with these organisms. Mediastinal lymphadenopathy, which is seen in most cases of histoplasmosis in patients with intact immune systems, is seen in fewer than 20% of cases in patients with AIDS.

In one study of patients with AIDS and diffuse histoplasmosis, half had normal chest radiographs. Of those with abnormal radiographs, the most common finding was a pattern of diffuse nodular opacities. In our review of the literature, pleural effusion due to culture-proven Histoplasma capsulatum has been documented only in 2 patients: one with idiopathic CD4 lymphocytopenia and another with progressive disseminated histoplasmosis.

Pearls

  • Histoplasmosis is the most common of the endemic mycoses in patients with AIDS, and disseminated disease is the most common presentation; radiographic findings are similar to those of miliary tuberculosis and PCP, both of which are potential co-infections.
  • Although rare, Histoplasma capsulatum infection should be considered in the differential diagnosis of pleural effusion in an immunocompromised host.

Case 4: Idiopathic hypereosinophilic syndrome

Juan C. Malpica Santiago, MD; Pedro A. Torrellas Ruiz, MD; Hiram Maldonado, MD, ACP Resident/Fellow Member; and Ricardo Fernandez Gonzalez, MD, FACP

The patient

A 34-year-old man with no medical history presented with dyspnea on exertion associated with cough productive of clear sputum for 3 days. He also described nausea without emesis and unintentional weight loss of 30 pounds in the prior 3 months. He reported no fever, chills, diarrhea, rhinorrhea, neuropathy, asthma, urticaria, or recent travel. He had a 4-pack-year smoking history and reported occasionally smoking crack cocaine.

Vital signs were remarkable for oxygen saturation by pulse oximetry of 91% on room air. Physical examination revealed cachexia and bilateral inspiratory rhonchi on lung auscultation. Complete blood count revealed significant elevation in absolute eosinophil count (6,090 cells/µL; white blood count, 29,000 cells/µL with 21% eosinophils), without anemia or thrombocytopenia. The erythrocyte sedimentation rate (16 mm/h) and lactate dehydrogenase level (683 U/L) were elevated. The remainder of the patient's serologic evaluation was unremarkable, including tests for HIV; cultures of the blood, urine, and sputum; B12, hepatic enzymes; IgE; and rheumatologic antibodies.

The chest radiograph showed a right lower lobe infiltrate. CT scan of the chest demonstrated right lower and middle lobe patchy infiltrates with surrounding ground glass opacities. CT of the abdomen and pelvis was negative. Flexible bronchoscopy with bronchoalveolar lavage was unrevealing for eosinophils, and washings with cultures were negative for bacteria, fungi, and mycobacterium. Stool was negative for ova and parasites. A bone marrow biopsy revealed a mildly hypercellular marrow with marked eosinophilia and no dyspoiesis to suggest a hematologic malignancy.

The diagnosis

The patient was diagnosed with idiopathic hypereosinophilic syndrome (IHES). IHES is a leukoproliferative disorder characterized by cytokine-induced overproduction of eosinophils of unknown origin. The diagnostic criteria include evidence of end-organ damage, exclusion of all other causes of eosinophilia, and sustained eosinophil count more than 1,500 cells/µL lasting longer than 6 months. This definition includes patients with IHES that is responsible for end-organ damage, for which treatment is quickly initiated to prevent further damage despite nonfulfillment of the 6-month time criterion.

There are no published data regarding the incidence and prevalence of IHES, although the syndrome is considered rare in adults and very rare in children. IHES predominantly affects men, with an estimated male-to-female ratio ranging between 4 and 9 to 1. There are more than 150 identified causes of eosinophilia. In most cases, diagnostic workup will lead to diagnosis of an allergic disorder or infection; schistosomiasis, filariasis, and human T-lymphotropic virus type 1 (HTLV-1) must be considered in Puerto Rico. Therapeutic management should be adjusted to disease. This patient responded to corticosteroids, which are the first line of treatment for IHES. In other patients, agents such as hydroxycarbamide, interferon-alpha, and imatinib can be used when steroid resistance is demonstrated or when steroid-sparing agents are necessary.

Pearls

  • Eosinophilia may be associated with many underlying causes; in most cases, diagnostic workup will lead to diagnosis of an allergic disorder or infection; schistosomiasis, filariasis, and HTLV-1 must be considered in Puerto Rico.
  • Idiopathic hypereosinophilic syndrome is a diagnosis of exclusion, but the most helpful clinical clues are sustained overproduction of eosinophils with evidence of end-organ damage.

Case 5: Fatal leptospirosis

Emmanuel Gonzalez Irizarry, MD; Jesse R. Aleman-Ortiz, MD, MPH; and William Rodriguez-Cintron, MD, MACP

The patient

A 48-year-old man with a history of hepatitis A and C and cocaine and opioid abuse was in his usual state of health until 1 week before admission, when he developed general malaise, anorexia, diffuse joint pain, myalgia, headaches, fever, and chills. He subsequently developed nausea, vomiting, and diarrhea. Two days before admission, he described a cough productive of yellow sputum with “dark spots,” which was associated with shortness of breath and pleuritic chest pain. The patient reported recent crack cocaine use; his homelessness had recently exposed him to the feces and urine of rats and stray dogs.

Initial chest imaging shows alveolar-reticular infiltrates Image courtesy of Dr William Rodriguez-Cintron
Initial chest imaging shows alveolar-reticular infiltrates. Image courtesy of Dr. William Rodriguez-Cintron.

Upon initial evaluation, the patient was hypotensive but fluid responsive. Physical examination was noteworthy for jaundice, scleral icterus with conjunctival suffusion, and dry oral mucosa. Initial laboratory examination revealed the following abnormalities: an acute drop in hemoglobin level from a baseline of 10.6 g/dL to 6.6 g/dL, acute renal failure, thrombocytopenia, and elevated levels of creatine phosphokinase (CPK) of 1,988 U/L (reference range, 5 to 169 U/L), lactic acid of 5.3 mmol/L (reference range, 0.5 to 2.2 mmol/L), and bilirubin of 14.9 mg/dL (reference range, 0.2 to 1.3 mg/dL). Alkaline phosphatase and liver enzyme levels were within normal range. Leptospira antibodies were negative. Urine toxicology was positive for cocaine and opioids. Initial chest imaging showed alveolar-reticular infiltrates (Figure 9).

Evidence of worsening airspace opacities suggestive of alveolar hemorrhage on follow-up chest radiograph Image courtesy of Dr William Rodriguez-Cintron
Evidence of worsening airspace opacities suggestive of alveolar hemorrhage, on follow-up chest radiograph. Image courtesy of Dr. William Rodriguez-Cintron.

The patient was started on fluids and broad-spectrum antibiotics and was subsequently intubated for respiratory decompensation. Copious blood was suctioned from his trachea, and follow-up chest radiography showed evidence of worsening airspace opacities suggestive of alveolar hemorrhage (Figure 10). Platelets and packed red blood cells were administered, but worsening oxygenation resulted in cardiac arrest and death.

The diagnosis

This patient's clinical manifestations, history, laboratory findings, and physical examination suggest the diagnosis of Weil's syndrome (severe leptospirosis), with associated multi-organ failure. Due to lack of a reference standard for diagnosis of leptospirosis, especially in the acute phase, a high index of suspicion is required to make the diagnosis based on epidemiologic exposure and physical manifestations.

Leptospirosis is a widespread zoonotic disease that occurs in both temperate and tropical regions. Human leptospirosis is a reportable disease in Puerto Rico. Between 2000 and 2009, approximately 15 to 100 cases of suspected leptospirosis were reported to the Puerto Rico Department of Health each year. In 2010, a total of 59 leptospirosis cases were reported, including 1 death. Barriers to determining the actual burden of leptospirosis in Puerto Rico include the unavailability of diagnostic testing on the island, no system of veterinary surveillance to detect animal cases, and no environmental surveillance to identify circulating serovars. If the Puerto Rico Department of Health's passive case reporting system captured all cases of leptospirosis, 3 to 9 reported deaths from 59 reported cases would have been expected, for a rate of 0.08 to 0.24 deaths per 100,000. These findings suggest that 60% to 90% of fatal leptospirosis cases are not reported, reflecting under-recognition of cases, under-reporting, or both.

The organism infects a variety of both wild and domestic animals, especially rodents, cattle, horses, swine, dogs, sheep, and goats. Humans are infected incidentally by contact with animal urine or infected soil or water. Rodents are the most important reservoirs for maintaining transmission. Infected rodents may shed the organism in their urine intermittently or continuously throughout life, resulting in contamination of the environment. Most cases are mild and self-limited or subclinical, while some are severe and potentially fatal. The illness generally presents with fever and constitutional symptoms. Conjunctival suffusion, which is a pathognomonic sign seen in about 30% of patients, is a frequently overlooked sign that is associated with leptospirosis. This develops toward the end of the early phase of the disease and is characterized by hyperemia of the conjunctival vessels along the palpebral fissures and chemosis that resembles conjunctivitis but does not involve inflammatory exudates. The presence of conjunctival suffusion has a high specificity (97%) and a high positive predictive value (83%) for identifying leptospirosis in the proper clinical scenario.

Weil's disease refers to severe, potentially fatal illness from leptospirosis and occurs in 5% to 10% of patients. Pulmonary symptoms occur in 20% to 70% of patients and are usually mild and without sequelae. The most common pulmonary symptom is dry cough. Pulmonary hemorrhage is a known potential complication. Severe pulmonary involvement of leptospirosis manifests itself as pulmonary hemorrhage, which usually has a rapid and severe course with high mortality rates; this has been reported from in 30% to 60% of cases. Hemoptysis, a manifestation of pulmonary hemorrhage, has been reported in 17% to 50% of patients. Empiric therapy includes penicillins and tetracyclines; however, most treatment is largely supportive.

Pearls

  • Weil's syndrome refers to a severe, potentially fatal leptospirosis infection characterized by jaundice and multiorgan failure.
  • The clinician should suspect leptospirosis in patients with specific clinical findings and history.

Conjunctival suffusion, a highly specific sign for leptospirosis, is a hyperemia of the conjunctival vessels along the palpebral fissures and chemosis that resembles conjunctivitis but does not involve inflammatory exudates.